Cd38 positive

Cd38 positive DEFAULT

CD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma

Multiple Myeloma and CD38: Background

Multiple myeloma (MM) is a neoplasm characterized by a clonal expansion of malignant plasma cells (PC) in the bone marrow (BM). MM arises from pre-malignant asymptomatic proliferation of PC, that are classified as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) (1). Patients with MGUS are characterized by low levels of serum M-protein (< 3 g/dL) and monoclonal PC in BM (< 10%), whereas patients with SMM display higher levels of serum M-protein (≥3 g/dL) and/or PC in the BM (≥10%). In contrast, diagnosis of MM includes the presence of end-organ damage associated with the presence of serum M-spike and/or monoclonal PC in the BM (2, 3). Malignant transformation of PC, that are derived from post-germinal center B cells, is usually driven by multiple genetic and environmental changes. Indeed, different genetic abnormalities have been detected in MM and play a role in the pathogenesis of MM, including (i) translocation of chromosome 14 (t[14;16] and t[14;4]), (ii) MYC amplification, (iii) activation of NRAS and KRAS, (iv) mutations in FGFR3 and TP53, and (v) inactivation of cyclin-dependent kinase inhibitors CDKN2A and CDKN2C (4, 5). MM accounts 1% of all cancer, and represents the second most common hematological malignancy, with 25,000–30,000 new cases per year and an incidence of 5 cases per 100,000 (6, 7). The median age of MM patients at diagnosis ranged from 66 to 70 years, and only 37% of patients display an age below 65 years (7). The median survival of relapsed MM patients has increased from 12 months (before 2000) to 24 months after 2000, due to the availability of effective treatments (8). Modern therapies, such as immunomodulatory drugs and proteasome inhibitors, have further prolonged the 5- and 10-years survival rates of MM patients, and a doubling of the median survival time has been observed in patients diagnosed in the last decade (8). However, prognosis of relapsed MM patients is still poor, and novel therapeutic approaches are urgently needed. In this context, CD38 represents a promising therapeutic target, since its expression is high and uniform on malignant PC, whereas it is relatively low on normal lymphoid and myeloid cells and on non-hematopoietic tissues. CD38 is a 45 KDa surface glycoprotein, firstly identified as an activation marker (9): successively the molecule was reported as an adhesion molecule, able to interact with endothelial CD31 (10). These finding highlighted the possibility that CD38 may act as a receptor, notwithstanding a structural ineptitude to do so. It was shown indeed that CD38 act as an accessory component of the synapse complex (11). CD38 was then identified as an ectoenzyme involved in the metabolism of extracellular nicotinamide adenine dinucleotide (NAD+) and cytoplasmic nicotinamide adenine dinucleotide phosphate (NADP) (12). The results is the production of Ca2+-mobilizing compounds, such as cyclic adenosine diphosphate [ADP] ribose, ADP ribose (ADPR) and nicotinic acid adenine dinucleotide phosphate. CD38 enzymatic activities were shown as able to rule the NAD+ levels and improve the function of proteasome inhibitors (13). Further, ADPR produced by CD38 can be further metabolized by the concerted action of CD203a/PC-1 and CD73, to produce the immunosuppressive molecule adenosine (ADO). This feature points out the role of CD38 in the escape of tumor cells from the control of the immune system (14).

CD38-Targeted Immunotherapeutic Strategies: Rationale, Applications and Limitations

It has been demonstrated that conventional therapies, such as vincristine and doxorubicin, induce the expression of multidrug resistance genes and p-glycoprotein in tumor cells, that become resistant to different drugs (15). Thus, conventional therapies may be combined with immunotherapeutic strategies targeting CD38 to improve their efficacy. Indeed, it has been already demonstrated that combined therapies simultaneously target multiple pathways and prevent escape/resistance mechanisms of tumor cells. Moreover, combination of tumor-specific mAbs and standard chemotherapy is already a standard-of-care in several hematologic (Hodgkin's lymphoma and CLL) and solid (breast cancer and colon carcinoma) tumors (16).

In the context of MM, we have recently demonstrated that, within the bone niche, only PCs express CD38 at high levels. Moreover, CD38 expression can be detected on monocytes and early osteoclast progenitors but not on osteoblasts and mature osteoclasts, thus suggesting that CD38 expression was lost during in vitro osteoclastogenesis. Accordingly, we found that Daratumumab inhibited in vitro osteoclastogenesis and bone resorption activity from BM total mononuclear cells of MM patients, targeting CD38 expressed on monocytes and early osteoclast progenitors (17). In addition, several studies reported that anti-CD38 mAbs are able to deplete CD38+ immunosuppressive cells, such as myeloid-derived suppressor cells, regulatory T cells and regulatory B cells, leading to an increased anti-tumor activity of immune effector cells (18, 19).Thus, these data provide a rationale for the use of an anti-CD38 antibody-based approach as treatment for MM patients.

However, CD38 is known to be also detectable on other normal cell subsets, such as NK cells, B cells and activated T cells and the use of anti CD38 abs could thus affect the activity of normal cells. NK cells specifically play a pivotal role for the therapeutic effects of anti-CD38 mAbs, since they mediated antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). This issue can be addressed by using anti-CD38 F(ab')2 fragments to protect normal cells from subsequent anti-CD38 mAb-mediated lysis, or by infusion of ex-vivo expanded NK cells (20).

Another possible limitation of CD38-targeted therapy may be represented by the variable expression of CD38 on malignant PC. In particular, CD38 expression may be downregulated following the first infusions of anti-CD38 mAbs, favoring immune escape and disease progression (21). On this regard, combined therapy has been proposed to increase CD38 expression on malignant cells, using a pan–histone deacetylase inhibitor (Panobinostat) (22) or all-trans reticnoic acid (ATRA) (23). These studies have demonstrated that anti-CD38 mAb-mediated ADCC dramatically increased in vitro after the treatment, following the up-regulation of CD38 expression on MM cells (22, 23).

Anti-CD38 treatment may also generate resistance and induce tumor immune escape, through the up-regulation of two complement inhibitor proteins, CD55 and CD59 on MM cells. However, Nijhof and coworkers have demonstrated that ATRA treatment is also able to reduce CD55 and CD59 expression on anti-CD38-resistant MM cells, thus supporting the use of a combined therapy to improve complement-mediated cytotoxicity (CDC) against malignant cells (21).

In the last years, several novel immunotherapeutic approaches have been tested for MM patients, using CD38 as target, both in preclinical models and in clinical trials. These strategies include (i) mAbs specific for CD38, (ii) radioimmunotherapy, using radionuclides targeted to CD38 molecule, and (iii) adoptive cell therapy, using T cells transfected with a chimeric antigen receptor (CAR) specific for CD38.

Anti-CD38 mAbs

Development of mAbs against CD38 started in 1990 and anti-CD38 mAbs have been tested as immunotherapeutic strategy for MM patients, so far with limited beneficial effects. The anti-tumor effect of anti-CD38 mAbs is related to their ability to induce ADCC, CDC and ADCP of opsonized CD38+ cells. Moreover, anti-CD38 mAbs can induce a direct apoptosis of CD38+ MM cells via Fc-γ receptor-mediated crosslinking (24). Crosslinking of anti-CD38 mAbs on MM cells leads to clustering of cells, phosphatidylserine translocation, loss of mitochondrial membrane potential, and loss of membrane integrity. This effect is called homotypic aggregation, and may be related or not to caspase-3 cleavage (25). The mechanism(s) of action of anti-CD38 mAbs on MM cells are represented in Figure 1.

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Figure 1. Schematic representation of the mechanism(s) of action of anti-CD38 mAbs on MM cells.

Here, we summarized novel findings obtained using anti-CD38 mAbs as therapeutic strategy for MM in vitro, in preclinical studies and, finally, in clinical trials.

Daratumumab

Daratumumab is a human anti-CD38 mAb, which is able to trigger ADCC and CDC in vitro against CD38+ tumor cells, using either autologous or allogeneic effector cells. Daratumumab-mediated ADCC and CDC in vivo is not affected by the presence of BM stromal cells, thus suggesting that this mAb can kill MM tumor cells in a tumor-preserving BM microenvironment. Moreover, Daratumumab is able to inhibit tumor growth in xenograft models at low doses (26). Another study demonstrated that Daratumumab is able to trigged programmed cell death (PCD) of MM CD38+ cells when cross-linked in vitro by secondary mAbs or via an FcγR. Moreover, in a syngeneic in vivo tumor model, Daratumumab is able to induce PCD of MM cells, through the cross-linking mediated by both inhibitory FcγRIIb and activating FcγRs. These data suggested that the therapeutic effect of Daratumumab may be at least in part related to the induction of PCD of MM cells through cross-linking (25). The interaction between soluble Daratumumab and FcRs appears critical for the action of the antibody. The marked polar aggregation is followed by a significant release of microvesicles (MV) (27). Generation of MV is a physiological event: the difference with the same MV after antibody treatment is the fact that they are covered with the therapeutic IgG. This makes their destination mandatory to FcR-expressing cells and tissues (28). CD38 is expressed at high levels in BM niche only by PC. However, its expression can be detected at lower levels also on monocytes and early osteoclast progenitors, but not on mature osteoblasts and osteoclasts, since CD38 expression is downregulated during in vitro osteoclastogenesis (17). Consistently, it has been demonstrated that Daratumumab reacts with CD38 expressed on monocytes and inhibited in vitro osteoclastogenesis and bone resorption activity from BM total mononuclear cells (MNC) of MM patients, by targeting CD38+ osteoclast progenitors. Thus, Daratumumab may be effective also to prevent osteoclastogenesis induced by MM (17). The anti-tumor efficacy of Daratumumab may be increased by the combination with immunomodulatory drugs. One study analyzed the combined effect of human anti-CD38 mAb Daratumumab and lenalidomide, a drug that is able stimulate the immune system and to induce apoptosis of tumor cells and inhibition of angiogenesis. They have demonstrated that effector cells derived from peripheral blood (PB) MNC from healthy individuals pretreated with lenalidomide displayed in vitro an increased ADCC mediated by Daratumumab against primary CD38+ MM cells and UM-9 MM cell line. Same results were obtained using BM MNC of MM patients, thus indicating that lenalidomide can increase Daratumumab-mediated lysis of MM cells by activating autologous effector cells within the natural environment of malignant cells. Finally, they have demonstrated an increased Daratumumab-dependent ADCC against MM cells using PB derived from lenalidomide-treated MM patients as effector cells. These data suggested that the combination of lenalidomide and Daratumumab may represent an effective novel therapeutic strategy for MM patients (29). This conclusion was confirmed by another study, where Daratumumab was combined with lenalidomide and bortezomib (30). Daratumumab induced lysis of (i) MM cells that were resistant to lenalidomide and bortezomib and (ii) primary MM cells using BM MNC derived from MM patients that were refractory to lenalidomide and/or bortezomib treatment. This study confirmed that lenalidomide (but not bortezomib) synergistically enhanced Daratumumab-mediated lysis of MM cells through activation of NK cells. Moreover, the combination of daratumumab with lenalidomide effectively reduced the growth of primary MM cells from a lenalidomide- and bortezomib-refractory patient in vivo using a xenograft model (30). We summarized the clinical results obtained with Daratumumab in a recent Review article (31).

Isatuximab

Isatuximab (formerly known as SAR650984) is a humanized anti-CD38 mAb that exerts a strong pro-apoptotic activity independent of cross-linking agents, and potent anti-tumor activity related to CDC, ADCC and ADCP. These functions are equivalent in vitro to those observed for rituximab in CD20+ and CD38+ models. Moreover, isatuximab is able to partially inhibit ADP-ribosyl cyclase activity of CD38, through an allosteric antagonism (32). Additional mechanism of action have been characterized by Jiang et al., who have demonstrated that isatuximab is able to induce homotypic aggregation-associated cell death in MM cells, that is related to the level of CD38 expression on cell surface and depends on actin cytoskeleton and membrane lipid raft (33). Isatuximab and its F(ab)'2 fragments also induce (i) apoptosis of MM cells highly expressing CD38, through the activation of caspase 3 and 7, (ii) lysosome-dependent cell death by enlarging lysosomes and increasing permeabilization of lysosomal membrane, and (ii) upregulation of reactive oxygen species. It has been also demonstrated that SAR650984-mediated killing of MM cells is enhanced by the antitumoral drug pomalidomide, even in MM cells resistant to pomalidomide/lenalidomide (33). Feng and coworkers have demonstrated that isatuximab is able to decrease the frequency of CD38hi Treg and to increase the frequency of CD4+CD25 T cells. Treatment with isatuximab downmodulate Foxp3 and IL10 in Tregs and restores proliferation and function of T cells. Furthermore, isatuximab increases MM cell lysis by CD8+ T and NK cells in vitro (34). MM cells are able to induce the expansion of CD38hi Tregs in vitro when cultured with CD4+CD25 T cells. In this context, isatuximab is able to inhibit the expansion of inducible Tregs by MM cells and stromal cells, by inhibiting cell-to-cell contact and release of TGFβ/IL10. Thus, this study demonstrated that isatuximab, through CD38 targeting, is able to revert MM-induced immunosuppression and to restore anti-MM immune effector cell functions (34). Finally, it has been demonstrated that isatuximab was effective to eradicate malignant cells in vivo in xenograft models of different hematological CD38+ human tumors, including MM. This anti-tumor activity was more potent than that of bortezomib in MM xenograft models set up using NCI-H929 and Molp-8 MM cell lines. More importantly, isatuximab demonstrated a potent pro-apoptotic activity against CD38+ human primary MM cells (32). Taken together, these findings supported the use of isatuximab in phase 1 clinical studies for MM patients, alone or in combination with other drugs such as pomalidomide or lenalidomide.

CD38-Specific Chimeric mAbs and Nanobodies

In the past, several anti-CD38 mAb have been developed and tested for their ability to induce ADCC and CDC against CD38+ MM cells. Stevenson and coworkers have developed a chimeric anti-CD38 mAb, composed by the Fab portion of OKT10 murine mAb linked to a human IgG1 Fc fragment. This chimeric mAb, but not the parental mAb, mediated ADCC using human mononuclear effector cells, and displayed limited side effects on other CD38+ cell populations (i.e., NK cells and granulocyte/macrophage or erythroid progenitor cells). Chimeric mAb induced ADCC using cells isolated from 14 MM patients subjected to various chemotherapeutic regimes, and such function was similar to that observed in normal individuals, thus suggesting that treatment with anti-CD38 chimeric antibody may be effective in these patients (35). Similarly, Ellis and coworkers developed a humanized IgG1 mAb and a chimeric mAb (composed by mouse Fab cross-linked to two human gamma 1 Fc fragments) against CD38. Both mAbs efficiently directed ADCC against CD38+ cell lines, without down-modulating CD38 expression or enzymatic activity, thus representing a promising therapeutic strategy against MM and other diseases involving CD38+ cells (36).

More recently, different studies have been aimed at the generation of novel mAbs targeting CD38. In one of these studies, a series of nanobodies against CD38 with high affinities have been generated. The authors identified the epitopes that bind these nanobodies on the carboxyl domain of CD38 molecule. Next, they binded these nanobodies to fluorescent proteins to quantify CD38 expression then confirming the higher CD38 expression on MM cells as compared to normal leukocytes. More importantly, they have generated an immunotoxin, binding nanobodies with a bacterial toxin, that displayed a highly selective cytotoxicity against patient-derived MM cells and MM cell lines, even at very low concentrations. Such effect can be further enhanced by stimulating CD38 expression using retinoid acid. These results suggested that these anti-CD38 nanobodies may represent a novel diagnostic and therapeutic tool for MM patients (37). The development of anti-CD38 nanobodies has been carried out also by Fumey and coworkers. They have identified 22 nanobody families specific for CD38 molecule from llamas immunized with recombinant non-glycosylated CD38 ecto-domain, using a phage display technology (38). They performed cross-blockade analyses by flow cytometry using CD38-transfected cells, and an in-tandem epitope binding using CD38 molecule immobilized on biosensors, demonstrating that these nanobody families recognize three different non-overlapping epitopes, with four nanobody families showing a complementary binding to Daratumumab. Three nanobody families inhibit the enzymatic activity of CD38 in vitro, while two other families act as enhancers. All nanobodies also recognized native CD38 on tumor cells and lymphoid cells (T, B, and NK cells), and some of them still recognized tumor cells after opsonization with daratumumab, thus suggesting that these nanobodies recognized a different epitope. Finally, fluorochrome-conjugated CD38 nanobodies efficiently reach CD38+ tumors in a rodent model within 2 h after intravenous injection, thus allowing in vivo tumor imaging. This study suggested that anti-CD38 nanobodies may be effective for the modulation of CD38 enzymatic activity and for the diagnosis of CD38-expressing tumors, also in patients treated with daratumumab (38). Barabas and colleagues have developed novel anti-CD38 mAbs by injecting an immune complex, composed by CD38 antigen and homologous anti-CD38 lytic IgG mAbs, in rabbits. Recipient rabbits produced mAbs with the same specificity against CD38 antigen. Such mAbs demonstrated in vitro a potent agglutinating, precipitating and lytic function. Moreover, in the presence of complement, donor and recipient rabbits' immune sera lysed CD38+ MM cells in vitro. Thus, they demonstrated that this “third vaccination” method has good potential for MM therapy (39). Moreover, they have demonstrated that passive immunization of SCID mice injected subcutaneously with human MM cells with heterologous anti-CD38 IgG antibody containing serum significantly decreased cancer growth in the presence of complement, thus confirming the efficacy of this methods also in preclinical models (40).

Radioimmunotherapy

Since malignant PC are very radiosensitive, CD38 has been used as target for radioimmunotherapy (RIT) in preclinical models of MM. Green and coworkers investigated both conventional RIT (directly radiolabeled antibody) and streptavidin-biotin pretargeted RIT (PRIT) directed against CD38 as therapeutic approach to deliver radiation doses sufficient for MM cell eradication. They demonstrated that the biodistribution was increased using PRIT as compared to conventional RIT. They achieved a tumor/blood ratio of 638:1 24 h after PRIT, whereas ratios never exceeded 1:1 with conventional RIT. (90)Yttrium absorbed dose displayed an excellent target/normal organ ratios (6:1 for kidney, lung and liver; 10:1 for whole body). Moreover, they observed an objective remission of MM in 100% of mice treated with doses ranging from 800 to 1,200 μCi of anti-CD38 pre-targeted (90)Y-DOTA-biotin 7 days after the treatment, with a complete remission at day 23, with undetectable tumor masses. Moreover, 100% of mice bearing MM xenografts treated with 800 μCi of anti-CD38 pre-targeted (90)Y-DOTA-biotin achieved a long-term tumor-free survival (more than 70 days) compared with 0% in the control group (41). Since immunogenicity and endogenous biotin blockade may limit the clinical translation of PRIT, the authors developed a new approach based on the use of an anti-CD38 bispecific fusion protein conjugated with 90Y. This protein eliminates the interference due to biotin and is less immunogenic, and demonstrated an excellent blood clearance and targeting of MM cells in xenograft models. Indeed, they demonstrated a high tumor-absorbed dose and, more importantly, a high tumor-to-normal organ dose ratios (7:1 for liver and 15:1 for lung and kidney), thus demonstrating that fusion protein targets tumor cells but not normal tissues. They obtained a 100% of complete remissions at day 12 and 80% of mice cured at optimal doses (1,200 μCi), thus demonstrating an efficacy of the fusion protein equal to streptavidin-biotin-based PRIT. Furthermore, bispecific proteins display a superior efficacy as compared to the latter method, in terms of overall survival, using lower radiation doses (600–1,000 μCi). Thus, bispecific PRIT represents an attractive candidate for clinical translation, especially for MM patients with refractory disease, which typically retained sensitivity to radiation (42). Teiluf and coworkers tested radioimmunoconjugates, consisting of the α-emitter 213Bi conjugated to anti-CD38 mAb in preclinical models of MM. 213Bi-anti-CD38 mAb was effective in the induction of DNA double-strand breaks in different MM cell lines, inducing apoptosis, cell cycle arrest and mitotic arrest, with subsequent mitotic catastrophe. The anti-tumor effect of therapeutic strategy correlated with the expression level of CD38 on MM cell lines. More importantly, they demonstrated that mice bearing MM xenografts treated with 213Bi-anti-CD38 mAb display a limited tumor growth via induction of apoptosis in tumor tissue, and a significantly prolonged survival compared to controls. Moreover, no signs of 213Bi-induced toxicity was observed in the major organ systems (43). These studies suggest that CD38-targeted RIT may represent a promising therapeutic tool for MM patients.

Cellular Therapy

Recent findings suggest that CD38 may represent a good target for antigen-specific adoptive cell therapy. Indeed, T cells expressing CAR have been successfully used in several clinical trials for solid and hematological tumors (44). Moreover, CAR T cells specific for different MM associated antigens, such as CS1 (45), B-cell maturation antigen (46), SLAMF7 (47), and CD19 (48) proved to be effective in preclinical models and/or in clinical trials. Mihara and coworkers developed anti-CD38 CAR T cells through retroviral vector-mediated transduction of the transmembrane domain of CD8α, the intracellular domains of 4–1BB and CD3ζ and anti-CD38 single-chain variable domain (scFv). Anti-CD38 CAR T cells displayed cytotoxic activity in vitro against either MM cell lines or primary MM cells isolated from patients. Thus, these cells may represent a powerful therapeutic tool in preclinical models of MM (49). This issue was addressed by Drent et al., who tested anti-CD38 CAR T cells in vivo using a xenotransplant model (using UM9 MM cell line), in which MM cells were grown in a humanized BM microenvironment. Anti-CD38 CAR T cells demonstrated a potent anti-tumor effect when administered intravenously or intratumorally, thus suggesting that these cells efficiently migrate, infiltrate, and eliminate human MM tumors growing in their natural niche. This study demonstrates that CAR mediated targeting of CD38+ MM cells represents a promising therapeutic strategy for MM patients (50). The same authors tested different antibody sequences, and demonstrated that anti-CD38 CART T cells are able to proliferate, to secrete pro-inflammatory cytokines and to lyse malignant cells, irrespective of the donor and antibody sequence. Moreover, they demonstrated that CAR T cells lyse the CD38+ fractions of CD34+ hematopoietic progenitor cells, monocytes, natural killer cells, and to a lesser extent T and B cells. However, they did not inhibit the outgrowth of progenitor cells into myeloid lineages and, furthermore, they were effectively controllable with a caspase-9-based suicide gene, thus guaranteeing the safety of this approach (51). In this line, the same authors recently developed anti-CD38 CAR T cells with a lower affinity for CD38 antigen. They used the “light-chain exchange” technology to combine the heavy chains of two high-affinity CD38 antibodies with 176 different germline light chains, thus generating more than 100 new antibodies with a lower affinity (10- to 1,000- fold) to CD38. Among them, they identified eight antibodies and they isolated the corresponding single-chain variable fragments to generate new anti-CD38 CAR T cells. These cells displayed a 1,000-fold reduced affinity for CD38, and were able to proliferate, produce Th1-like cytokines and, more importantly, to lyse CD38hi MM cells but not CD38low normal cells, either in vitro or in vivo. Thus, this approach allow to generate CAR T cells highly specific for tumor-associated antigens that are also expressed at low intensity by normal cells (52). These studies confirmed that anti-CD38 CAR T cells may represent a novel and effective therapeutic tool for MM patients. Indeed, three clinical trials based on CD38 CAR T cells are currently recruiting MM patients (www.clinicaltrials.gov).

A limitation on the use of CD38-specific CAR T cells may be represented by a possible toxicity of this approach, due to the presence of CD38 on normal cells, such as NK cells, activated T cells and B cells, as mentioned before. In this line, Drent et al. designed a novel class of doxycycline (DOX)-inducible CD38-specific CAR T cells, that are rapidly inactivated by low doses of DOX, allowing to control off-tumor effects within 24 h. Thus, this strategy adds a second level of safety in CAR T cell-mediated therapy of MM patients, allowing to control the activity of CAR T cells without destroying them permanently (53). Another possible limitation is represented by the variable expression of CD38 on myeloma cells. As mentioned before, ATRA may be administered in combination with CD38-specific CAR T cells to up-regulate CD38 expression on malignant cells and consequently to improve CAR T cell-mediated anti-tumor activity. In this line, Mihara et al. have demonstrated that ATRA increases the cytotoxic activity of anti-CD38 CAR T cells against (i) acute myeloid leukemia (AML) cell lines and (ii) primary AML blasts from patients (54).

On the other hand, the anti-tumor activity of CD38-specific CAR T cells may be enhanced through the combination of these cells with conventional therapies, such as checkpoint inhibitors. Indeed, it has been demonstrated that PD-1 inhibitor pembrolizumab (PEM) increased and/or prolonged detection of circulating anti-CD19 CAR T cells in acute lymphoblastic leukemia (ALL) patients. Consequently, anti-tumor activity of CAR T cells was dramatically improved in PEM-treated patients (55).

Conclusions

The findings here reported confirmed that CD38 represents a good target for immunotherapeutic approaches for MM patients. Indeed, the efficacy of therapeutic strategies based on the use of mAbs or CAR T cells specific for CD38 has been demonstrated in vitro and in preclinical studies. More importantly, some of these therapeutic approaches have already been translated to the clinic, with promising results either as monotherapy or in combination with chemotherapeutic drugs. Currently, 23 clinical trials based on CD38 as target are ongoing (3 not yet recruiting, 12 recruiting, 6 active, and 2 completed, www.clinicaltrials.gov, Table 1).

Response rates for ongoing clinical trials with available clinical data are reported in Table 2. These studies confirmed that the combination of anti-CD38 mAbs with conventional therapies dramatically improved the clinical outcome of MM patients (56–59).Thus, further studies aimed at the characterization of novel combined therapies that include anti-CD38 immune effectors might be pivotal to design effective clinical strategies to increase progression-free and overall survival of MM patients.

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Table 2. Response rates in CD38-targeted ongoing clinical trials.

Author Contributions

FM analyzed data present in the literature and wrote the manuscript. ALH, FC, NG, FMal and VP contributed to the writing of the final version of the manuscript.

Funding

This work was supported by the Associazione Italiana per la Ricerca sul Cancro under IG2017 Grant (id. 20299), the International Myeloma Foundation under 2018 Brian D. Novis Senior Research Grant, Associazione Italiana per la Ricerca sul Cancro IG 17273 to VP and grant from Compagnia San Paolo to FMal. FMal acknowledges the help and assistance of the non-profit Fondazione Ricerca Molinete (Torino, Italy).

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: CD38, multiple myeloma, immunotherapy, preclinical models, clinical trials

Citation: Morandi F, Horenstein AL, Costa F, Giuliani N, Pistoia V and Malavasi F (2018) CD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma. Front. Immunol. 9:2722. doi: 10.3389/fimmu.2018.02722

Received: 15 June 2018; Accepted: 05 November 2018;
Published: 28 November 2018.

Edited by:

Rayne Rouce, Baylor College of Medicine, United States

Copyright © 2018 Morandi, Horenstein, Costa, Giuliani, Pistoia and Malavasi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Fabio Morandi, [email protected]

These authors have contributed equally to this work

Sours: https://www.frontiersin.org/articles/10.3389/fimmu.2018.02722/full

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Useful Links

    USACD38
    OMIM, Johns Hopkin University
    Referenced article focusing on the relationship between phenotype and genotype.

    USACD38
    International Cancer Genome Consortium.
    Summary of gene and mutations by cancer type from ICGC

    USACD38
    Cancer Genome Anatomy Project, NCI
    Gene Summary

    UKCD38
    COSMIC, Sanger Institute
    Somatic mutation information and related details

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    GEO Profiles, NCBI
    Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.

Latest Publications: CD38 (cancer-related)

Sheng Y, Ji Z, Zhao H, et al.
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OBJECTIVES: Epigenetic modifiers were important players in the development of haematological malignancies and sensitivity to therapy. Mutations of SET domain-containing 2 (SETD2), a methyltransferase that catalyses the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukaemia progression and resistance to therapy targeting on BCR-ABL remain unclear.
MATERIALS AND METHODS: The level of SETD2 in imatinib-sensitive and imatinib-resistant chronic myeloid leukaemia (CML) cells was examined by immunoblotting and quantitative real-time PCR. We analysed CD34
RESULTS: SETD2 was found to act as a tumour suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukaemic stem cell enrichment in CML cell lines. Treatment with JIB-04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell imatinib sensitivity and enhanced the chemotherapeutic effect.
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Bright SA, Byrne AJ, Vandenberghe E, et al.
Selected nitrostyrene compounds demonstrate potent activity in chronic lymphocytic leukaemia cells, including those with poor prognostic markers.
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The nitrostyrene scaffold was previously identified as a lead target structure for the development of effective compounds targeting Burkitt's lymphoma. The present study aimed to develop these compounds further in haematological malignancies, including chronic lymphocytic leukaemia (CLL). Cellular viability, flow cytometry and lactate dehydrogenase assays, amongst others, were used to examine the effects of nitrostyrene compounds on CLL cells, including a cell line representing disease with poor prognosis (HG‑3) and in ex vivo CLL patient samples (n=14). The results demonstrated that two representative nitrostyrene compounds potently induced apoptosis in CLL cells. The pro‑apoptotic effects of the compounds were found to be reactive oxygen species and caspase‑dependent, and had minimal effects on the viability of normal donor peripheral blood mononuclear cells. Nitrostyrene compounds exhibited synergistic augmentation of apoptosis when combined with the phosphatidylinositol 3‑kinase inhibitor idelalisib and demonstrated potent toxicity in ex vivo CLL cells, including those co‑cultured with bone marrow stromal cells, making them more resistant to apoptosis (n=8). These compounds also demonstrated activity in samples from patients with poor prognostic indicators; unmutated immunoglobulin heavy chain genes, expression of CD38 and deletions in chromosomes 17p and 11q. These results suggest that this class of pharmaceutically active compounds offer potential in the treatment of CLL.


Valiollahi E, Ribera JM, Genescà E, Behravan J
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Acute lymphoblastic leukemia (ALL) is a malignant transformation with uncontrolled proliferation of lymphoid precursor cells within bone marrow including a dismal prognosis after relapse. Survival of a population of quiescent leukemia stem cells (LSCs, also termed leukemia-initiating cells (LICs)) after treatment is one of the relapse reasons in Ph


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Kim KH, Cheong HJ, Lee MY, et al.
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AIM: Cytotoxic chemotherapy-based treatment of multiple myeloma (MM) is not curative, and the disease eventually recurs. This is partially because although currently available anti-MM strategies are effective in targeting the bulk of tumor cells, they do not target the tumor-initiating subpopulation of cancer stem cells. This study investigated the prevalence and biological functions of side population (SP) cells in MM cell lines including RPMI8226, ARH77, MM.1R and IM 9.
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Lu W, Ding Z
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Fedele PL, Willis SN, Liao Y, et al.
IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos.
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Nagant C, Casula D, Janssens A, et al.
Easy discrimination of hematogones from lymphoblasts in B-cell progenitor acute lymphoblastic leukemia patients using CD81/CD58 expression ratio.
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METHODS: A total of 82 bone marrow samples (39 BCP-ALL and 43 patients with HG) were analyzed using MFC. Mean fluorescence intensity (MFI) was measured for ten markers commonly used in hematology laboratories: CD45, CD19, CD10, CD34, CD38, CD20, CD22, CD58, CD81, and CD123. Statistical comparison of the MFI between LB and HG was performed. The presence on LB of aberrant expression of myeloid and/or T-cell markers was also investigated.
RESULTS: Qualitative pattern expression of antigens showed overexpression on LB of CD58, CD22, CD34, CD10 and underexpression of CD81, CD45, CD38 when compared to HG. Expression of CD123 was positive in 34% of BCP-ALL LB and always absent on HG. Aberrant antigen expression (myeloid and/or T-cell marker) including CD123 was observed in 58% of BCP-ALL patients. The use of a MFI antigen ratio of the most discriminating markers (CD81/CD58) (analysis of variance, P < 0.005) increased the distinction of LB versus HG with a high specificity and sensitivity as demonstrated by the use of ROC curve analysis (AUC of CD81/CD58: 0.995).
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Dong Q, Lv C, Zhang G, et al.
Impact of RNA‑binding motif 3 expression on the whole transcriptome of prostate cancer cells: An RNA sequencing study.
Oncol Rep. 2018; 40(4):2307-2315 [PubMed] Related Publications

RNA‑binding motif 3 (RBM3) is a cold‑shock protein that has been previously shown to attenuate cancer stem cell‑like features in prostate cancer (PCa) cells. However, the mechanism underlying RBM3 regulation in PCa cells is largely unknown. The present study investigated the impact of RBM3 expression on the whole transcriptome of PCa cells using high‑throughput RNA sequencing (RNA‑seq). Differentially expressed genes (DEGs) that were identified through RNA‑seq were applied to Gene Ontology (GO), pathway analysis, pathway‑action networks and protein‑protein interaction network analysis. GO and pathway ananlyses showed that RBM3 expression was associated with several metabolism pathways. Combining GO analysis and pathway analysis, certain DEGs, including phospholipase A2 group IIA (PLA2G2A), PLA2G2F, PLA2G4C, endothelin 1, cytochrome P450 family 2 subfamily B member 6, G protein subunit γ5, nitric oxide synthase 3 and CD38 molecule, were shown to be closely associated with RBM3 regulation in PCa cells. Furthermore, the changes in expression of selected genes upon RBM3‑knockdown in RNA‑seq were confirmed by separate reverse transcription‑quantitative‑polymerase chain reaction, validating the results of RNA‑seq. Thus, the present study provides a series of valuable reference genes and pathways for the future study of the pathogenic role of RBM3 in the development of PCa.


Gentil M, Hugues P, Desterke C, et al.
Aryl hydrocarbon receptor (AHR) is a novel druggable pathway controlling malignant progenitor proliferation in chronic myeloid leukemia (CML).
PLoS One. 2018; 13(8):e0200923 [PubMed] Free Access to Full ArticleRelated Publications

Aryl Hydrocarbon Receptor (AHR) is an ubiquitous basic helix-loop-helix transcription factor, which is ligand-activated and involved in numerous biological processes including cell division, cell quiescence and inflammation. It has been shown that AHR is involved in normal hematopoietic progenitor proliferation in human cells. In addition, loss of AHR in knockout mice is accompanied by a myeloproliferative syndrome-like disease, suggesting a role of AHR in hematopoietic stem cell (HSC) maintenance. To study the potential role of AHR pathway in CML progenitors and stem cells, we have first evaluated the expression of AHR in UT-7 cell line expressing BCR-ABL. AHR expression was highly reduced in UT-7 cell expressing BCR-ABL as compared to controls. AHR transcript levels, quantified in primary peripheral blood CML cells at diagnosis (n = 31 patients) were found to be significantly reduced compared to healthy controls (n = 15). The use of StemRegenin (SR1), an AHR antagonist, induced a marked expansion of total leukemic cells and leukemic CD34+ cells by about 4- and 10-fold respectively. SR1-treated CML CD34+ cells generated more colony-forming cells and long-term culture initiating cell (LTC-IC)-derived progenitors as compared to non-SR1-treated counterparts. Conversely, treatment of CML CD34+ cells with FICZ, a natural agonist of AHR, induced a 3-fold decrease in the number of CD34+ cells in culture after 7 days. Moreover, a 4-day FICZ treatment was sufficient to significantly reduce the clonogenic potential of CML CD34+ cells and this effect was synergized by Imatinib and Dasatinib treatments. Similarly, a 3-day FICZ treatment contributed to hinder significantly the number of LTC-IC-derived progenitors without synergistic effect with Imatinib. The analysis of molecular circuitry of AHR signaling in CML showed a transcriptional signature in CML derived CD34+ CD38- primitive cells with either low or high levels of AHR, with an upregulation of myeloid genes involved in differentiation in the "AHR low" fraction and an upregulation of genes involved in stem cell maintenance in the "AHR high" fraction. In conclusion, these findings demonstrate for the first time that down-regulation of AHR expression, a major cell cycle regulator, is involved in the myeloproliferative phenotype associated with CML. AHR agonists inhibit clonogenic and LTC-IC-derived progenitor growth and they could be used in leukemic stem cell targeting in CML.


Vetro C, Haferlach T, Jeromin S, et al.
Identification of prognostic parameters in CLL with no abnormalities detected by chromosome banding and FISH analyses.
Br J Haematol. 2018; 183(1):47-59 [PubMed] Related Publications

Chronic Lymphocytic Leukaemia (CLL) is a heterogeneous disease with a clinical course dependent on cytogenetic features. However, in 15-20% of cases both chromosome banding and fluorescence in situ hybridisation analyses do not show any kind of abnormality. With the aim to identify dependable molecular prognostic factors in this subgroup, we performed a comprehensive analysis on 171 patients including genomic arrays (comparative genomic hybridisation and single nucleotide polymorphism), immunoglobulin heavy chain variable region genes (IGHV) status, flow cytometry and targeted sequencing. Genomic arrays detected 73 aberrations in 39 patients (23%). Most frequently, patients had 1 aberration (25/171; 15%), while 14 patients (8%) had at least 2 aberrations. IGHV status was unmutated in 53/171 (31%) patients. SF3B1 was the most frequently mutated gene (26/171 patients; 15%), followed by NOTCH1 (15/171; 9%). At univariate analysis, an adverse impact on time to treatment (TTT) was evident for SF3B1 mutations, higher white blood cell count, higher CLL cells percentage by flow cytometry, CD38 positivity, IGHV unmutated status and at least 2 genomic array abnormalities. Of these, SF3B1 mutations, CLL cells percentage, IGHV unmutated status and number of genomic array aberrations maintained their impact in multivariate analysis. In conclusion, by integrating genomic and molecular data, we identified patients at higher risk for treatment need.


Mueller N, Wicklein D, Eisenwort G, et al.
CD44 is a RAS/STAT5-regulated invasion receptor that triggers disease expansion in advanced mastocytosis.
Blood. 2018; 132(18):1936-1950 [PubMed] Article available free on PMC after 01/11/2019 Related Publications

The Hermes receptor CD44 is a multifunctional adhesion molecule that plays an essential role in the homing and invasion of neoplastic stem cells in various myeloid malignancies. Although mast cells (MCs) reportedly express CD44, little is known about the regulation and function of this receptor in neoplastic cells in systemic mastocytosis (SM). We found that clonal CD34


Skerget M, Skopec B, Zadnik V, et al.
CD56 Expression Is an Important Prognostic Factor in Multiple Myeloma Even with Bortezomib Induction.
Acta Haematol. 2018; 139(4):228-234 [PubMed] Related Publications

OBJECTIVES: In this retrospective study, we evaluated the impact of CD56, CD117, and CD28 expression on clinical characteristics and survival in newly diagnosed myeloma patients treated with bortezomib-based induction therapy.
METHODS: We analyzed 110 myeloma patients. Immunophenotype was determined using panels consisting of CD19/CD38/CD45/CD56/CD138 and CD20, CD28, and CD117 were used additionally. All samples were tested for recurrent chromosomal aberrations.
RESULTS: CD56, CD117, and CD28 expression rates were 71, 6, and 68%, respectively. The lack of CD56 expression was associated with light chain myeloma. The lack of CD117 expression was associated with elevated creatinine levels (p = 0.037). We discovered the correlation between CD 28 expression and female gender. The median progression-free survival (PFS) for patients with revised International Staging System stage 2 disease with CD56 expression or the lack of CD56 expression was 20.5 vs. 13.8 months (p = 0.03). In patients undergoing autologous hematopoietic stem cell transplantation (aHSCT), we found no difference in PFS and overall survival regarding the CD56 expression. We found no impact of CD117 and CD28 expression on PFS in patients regarding aHSCT.
CONCLUSIONS: Induction treatment incorporating bortezomib diminishes the negative impact of the lack of CD117 expression and aberrancy of CD28 but does not overcome the negative impact of the lack of CD56 expression.


Yeong J, Lim JCT, Lee B, et al.
High Densities of Tumor-Associated Plasma Cells Predict Improved Prognosis in Triple Negative Breast Cancer.
Front Immunol. 2018; 9:1209 [PubMed] Article available free on PMC after 01/11/2019 Related Publications

Breast cancer is the most common malignancy affecting women, but the heterogeneity of the condition is a significant obstacle to effective treatment. Triple negative breast cancers (TNBCs) do not express HER2 or the receptors for estrogen or progesterone, and so often have a poor prognosis. Tumor-infiltrating T cells have been well-characterized in TNBC, and increased numbers are associated with better outcomes; however, the potential roles of B cells and plasma cells have been large. Here, we conducted a retrospective correlative study on the expression of B cell/plasma cell-related genes, and the abundance and localization of B cells and plasma cells within TNBCs, and clinical outcome. We analyzed 269 TNBC samples and used immunohistochemistry to quantify tumor-infiltrating B cells and plasma cells, coupled with NanoString measurement of expression of immunoglobulin metagenes. Multivariate analysis revealed that patients bearing TNBCs with above-median densities of CD38


Drent E, Poels R, Mulders MJ, et al.
Feasibility of controlling CD38-CAR T cell activity with a Tet-on inducible CAR design.
PLoS One. 2018; 13(5):e0197349 [PubMed] Article available free on PMC after 01/11/2019 Related Publications

Recent clinical advances with chimeric antigen receptor (CAR) T cells have led to the accelerated clinical approval of CD19-CARs to treat acute lymphoblastic leukemia. The CAR T cell therapy is nevertheless associated with toxicities, especially if the CARs are not entirely tumor-specific. Therefore, strategies for controlling the CAR T cell activity are required to improve their safety profile. Here, by using the multiple myeloma (MM)-associated CD38 molecule as target molecule, we tested the feasibility and utility of a doxycycline (DOX) inducible Tet-on CD38-CAR design to control the off-target toxicities of CAR T cells. Using CARs with high affinity to CD38, we demonstrate that this strategy allows the proper induction of CD38-CARs and CAR-mediated T cell cytotoxicity in a DOX-dose dependent manner. Especially when the DOX dose was limited to 10ng/ml, its removal resulted in a relatively rapid decay of CAR- related off-tumor effects within 24 hours, indicating the active controllability of undesired CAR activity. This Tet-on CAR design also allowed us to induce the maximal anti-MM cytotoxic activity of affinity-optimized CD38-CAR T cells, which already display a low toxicity profile, hereby adding a second level of safety to these cells. Collectively, these results indicate the possibility to utilize this DOX inducible CAR-design to actively regulate the CAR-mediated activities of therapeutic T cells. We therefore conclude that the Tet-on system may be more advantageous above suicide-genes to control the potential toxicities of CAR T cells without the need to destroy them permanently.


Blatt K, Menzl I, Eisenwort G, et al.
Phenotyping and Target Expression Profiling of CD34
Neoplasia. 2018; 20(6):632-642 [PubMed] Article available free on PMC after 01/11/2019 Related Publications

Leukemic stem cells (LSCs) are an emerging target of curative anti-leukemia therapy. In acute lymphoblastic leukemia (ALL), LSCs frequently express CD34 and often lack CD38. However, little is known about markers and targets expressed in ALL LSCs. We have examined marker- and target expression profiles in CD34


De Bie J, Demeyer S, Alberti-Servera L, et al.
Single-cell sequencing reveals the origin and the order of mutation acquisition in T-cell acute lymphoblastic leukemia.
Leukemia. 2018; 32(6):1358-1369 [PubMed] Article available free on PMC after 01/11/2019 Related Publications

Next-generation sequencing has provided a detailed overview of the various genomic lesions implicated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). Typically, 10-20 protein-altering lesions are found in T-ALL cells at diagnosis. However, it is currently unclear in which order these mutations are acquired and in which progenitor cells this is initiated. To address these questions, we used targeted single-cell sequencing of total bone marrow cells and CD34


Papageorgiou SG, Kontos CK, Tsiakanikas P, et al.
Elevated miR-20b-5p expression in peripheral blood mononuclear cells: A novel, independent molecular biomarker of favorable prognosis in chronic lymphocytic leukemia.
Leuk Res. 2018; 70:1-7 [PubMed] Related Publications

MicroRNA-20b-5p (miR-20b-5p) is part of the miR-106a/363 cluster and a member of the cancer-related miR-17 family. miR-20b-5p regulates important transcription factors, including hypoxia-inducible factor 1 (HIF1) and signal transducer and activator of transcription 3 (STAT3). Recently, the dysregulation of miR-20b-5p expression has been observed in many B-cell lymphomas and T-cell leukemias. In this research study, we examined the putative prognostic value of miR-20b-5p in CLL. Therefore, total RNA was isolated from peripheral blood mononuclear cells (PBMCs) collected from 88 CLL patients; next, total RNA was polyadenylated and first-strand cDNA was synthesized, using an oligo-dT-adapter primer. miR-20b-5p expression was quantified using an in-house-developed real-time quantitative PCR assay. Kaplan-Meier OS analysis and bootstrap univariate Cox regression showed that high miR-20b-5p expression predicts better OS for CLL patients (p < 0.001). Interestingly, miR-20b-5p overexpression retains its favorable prognostic role in CLL patients of intermediate risk or stratified according to established prognostic factors [CD38 expression and mutational status of the immunoglobulin heavy chain variable (IGHV) region]. In conclusion, miR-20b-5p is a potential independent molecular biomarker of favorable prognosis in CLL.


Liu Y, Wang Y, Yang J, et al.
ZAP-70 in chronic lymphocytic leukemia: A meta-analysis.
Clin Chim Acta. 2018; 483:82-88 [PubMed] Related Publications

BACKGROUND: Recent studies have reported that zeta-chain-associated protein kinase 70 (ZAP-70) expression plays a prognostic role in chronic lymphocytic leukemia (CLL). However, these results remain controversial. Thus, we performed a meta-analysis to clarify the prognostic value of ZAP-70 expression in CLL.
MATERIALS AND METHODS: Relevant studies were searched in PubMed, Embase, Cochrane library, and Web of Science up to January 2018. Clinicopathological features and prognostic data were extracted from the studies. We pooled estimates and 95% confidence intervals (CIs) and estimated the heterogeneity of studies using Mantel-Haenszel or DerSimonian and Laird method.
RESULTS: Twelve studies that included 1956 patients with CLL were eligible for inclusion. The pooled results revealed that increased ZAP-70 expression was significantly associated with poor overall survival (hazard ratio [HR] = 2.48, 95% CI: 1.72-3.59, P = 0.019, I
CONCLUSIONS: Our findings indicated that ZAP-70 was a strong prognostic biomarker for patients with CLL.


Ikejiri F, Honma Y, Okada T, et al.
Cotylenin A and tyrosine kinase inhibitors synergistically inhibit the growth of chronic myeloid leukemia cells.
Int J Oncol. 2018; 52(6):2061-2068 [PubMed] Related Publications

The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) has substantially extended patient survival. However, TKIs do not effectively eliminate CML stem cells. In fact, CML stem cells persist and cause relapse in the majority of patients upon discontinuation of the drug treatment. Transcriptomic and proteomic analyses have revealed that p53 and c-Myc play defining roles in CML stem cell survival, suggesting that the dual targeting of p53 and c-Myc may selectively eliminate stem cells in patients with CML. Since the downregulation of c-Myc and then upregulation of p21 (a target gene of p53) are commonly observed during the differentiation of acute myeloid leukemia cells induced by differentiation inducers, we hypothesized that differentiation-inducing agents may be useful in regulating c-Myc and p53 expression in CML cells. In the present study, we demonstrate that some differentiation-inducing agents effectively suppress the self-renewal ability of CML cells, and that the combination of these inducers with TKIs results in significantly greater inhibitory effects on CML cell growth compared to the use of TKIs or the inducer alone. The KU812 cells were treated with various concentrations of the inducers in the presence or absence of 30 nM imatinib for 4 days. Among the differentiation inducers we tested, cotylenin A (CN-A) was the most potent at inhibiting the self-renewal ability of the CML cells. CN-A induced the robust expression of CD38, a marker of committed progenitor and more differentiated myelomonocytic cells, and rapidly suppressed c-Myc expression and upregulated p21 expression in CML cells. Thus, these results suggest that CN-A may have potential to promote the elimination of stem cells in CML.


Bae J, Hideshima T, Tai YT, et al.
Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors.
Leukemia. 2018; 32(9):1932-1947 [PubMed] Article available free on PMC after 01/11/2019 Related Publications

Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138


Papageorgiou SG, Kontos CK, Diamantopoulos MA, et al.
MicroRNA-155-5p Overexpression in Peripheral Blood Mononuclear Cells of Chronic Lymphocytic Leukemia Patients Is a Novel, Independent Molecular Biomarker of Poor Prognosis.
Dis Markers. 2017; 2017:2046545 [PubMed] Article available free on PMC after 01/11/2019 Related Publications

MicroRNA-155-5p (miR-155-5p) is a proinflammatory, oncogenic miRNA, involved in various physiological processes, including hematopoiesis, immunity, inflammation, and cell lineage differentiation. It regulates important transcription factors, such as E2F2, hypoxia-inducible factor 1 (HIF1), and FOXO3. Recently, the dysregulation of miR-155-5p expression has been linked to chronic lymphocytic leukemia (CLL) pathogenesis. In this research study, we investigated the potential diagnostic and prognostic value of miR-155-5p in CLL. To achieve our goal, we isolated total RNA from peripheral blood mononuclear cells (PBMCs) collected from 88 CLL patients and 36 nonleukemic blood donors and performed polyadenylation of total RNA and reverse transcription. Next, we quantified miR-155-5p levels using an in-house-developed real-time quantitative PCR method, before proceeding to extensive biostatistical analysis. Thus, it appears that miR-155-5p is significantly overexpressed in PBMCs of CLL patients and can distinguish them from nonleukemic population. Kaplan-Meier OS analysis and bootstrap univariate Cox regression showed that high miR-155-5p expression predicts inferior OS for CLL patients (


Zhao HY, Song Y, Cao XN, et al.
Leukemia-propagating cells demonstrate distinctive gene expression profiles compared with other cell fractions from patients with de novo Philadelphia chromosome-positive ALL.
Ann Hematol. 2018; 97(5):799-811 [PubMed] Related Publications

Relapse remains one of the major obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph


Aoyama Y, Kodaka T, Zushi Y, et al.
Composite Lymphoma as Co-occurrence of Advanced Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Carrying Trisomy 12 and t(14;18) and Peripheral T-cell Lymphoma.
J Clin Exp Hematop. 2018; 58(1):27-31 [PubMed] Article available free on PMC after 01/11/2019 Related Publications

Composite lymphoma is defined as the co-occurrence of two types of lymphoma, comprising 1-4% of lymphomas, and the association of B-cell-type chronic lymphocytic leukemia (B-CLL)/small lymphocytic lymphoma and peripheral T-cell lymphoma (PTCL) is rare. Here, we report a case (77-year-old woman) of advanced B-CLL complicated by newly appearing PTCL. Two years after the onset of B-CLL, CLL cells acquired CD38 antigen expression and the disease entity became CLL/prolymphocytic leukemia. Trisomy 12 and t(14;18) karyotypes were observed. Five years after the onset of B-CLL, large abnormal cells with convoluted nuclei appeared in the peripheral blood and rapidly increased in number. These cells were positive for CD3, CD4, CD5, CD30 (partially), CD56, and αβ-type T-cell receptor (TCR), in which PCR demonstrated monoclonal TCR-γ gene rearrangement. An additional diagnosis of PTCL, not otherwise specified was made. We treated her with an R-CHOP regimen, resulting in the marked reduction of B-CLL cells but progressive PTCL. Brentuximab vedotin had a transient effect, but the patient died of sepsis due to residual PTCL and pancytopenia. This case is highly informative for tumor biology of B-CLL in terms of emergence of both chromosomal abnormalities and PTCL with progression of this leukemia.


Kong YL, Huang Y, Wu JZ, et al.
Expression of autophagy related genes in chronic lymphocytic leukemia is associated with disease course.
Leuk Res. 2018; 66:8-14 [PubMed] Related Publications

Autophagy leads cells to different fates in various cell types and under diverse contexts. Chronic lymphocytic leukemia (CLL), an incurable hematologic neoplasm, has highly variable course and its heterogeneity prompts interest in exploring autophagic trajectories in CLL. We detected the mRNA levels of two autophagy-related genes, BECN1 and ATG5, assessed the association between expression levels and clinical characteristics, and did survival analysis. One hundred and six patients with CLL and fifty healthy controls were enrolled in the present study. CLL samples were found higher expression levels of BECN1 and ATG5 mRNA compared with healthy controls. Further confirmation at the protein level performed in a small cohort of patients, which included Beclin1, ATG5 and LC3-II showed the same trend. What's more, high expression at the mRNA level correlated with early Binet stage, isolated 13q deletion and negative CD38, which were associated with favor prognosis, suggesting that autophagy differs in CLL due to the presence of heterogeneity and high levels of these two genes may reflect better outcomes. Survival analysis did show patients with high expression of ATG5 mRNA had longer treatment free survival from the date of sampling.


Sours: http://www.cancerindex.org/geneweb/CD38.htm
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CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia

Employing a multicolour flow cytometry assay, 133 B-chronic lymphocytic leukaemia (B-CLL) cases were analysed for surface expression of CD38. Based on a cut-off value of 20%, CLL patients were categorised into a CD38-positive (> or = 20%, n = 56) and a CD38-negative subgroup (< 20%, n = 77) and separately analysed for clinical and laboratory parameters. Patients in the CD38-positive cohort were characterised by an unfavourable clinical course with a more advanced disease stage, poor responsiveness to chemotherapy, short time to initiation of first treatment and shorter survival. In contrast, the CD38- negative group required minimal or no treatment, remained treatment-free for a longer time period and had prolonged survival (P < 0.05). CD38 expression was a robust marker in the majority of patients in that it was stable over time and not significantly influenced by chemotherapy. In conclusion, our data confirm recent studies suggesting a role of CD38 as a predictor of clinical outcome in patients with B-CLL.

Sours: https://pubmed.ncbi.nlm.nih.gov/11840260/
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CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia

Abstract

Employing a multicolour flow cytometry assay, 133 B-chronic lymphocytic leukaemia (B-CLL) cases were analysed for surface expression of CD38. Based on a cut-off value of 20%, CLL patients were categorised into a CD38-positive (⩾20%, n = 56) and a CD38-negative subgroup (<20%, n = 77) and separately analysed for clinical and laboratory parameters. Patients in the CD38-positive cohort were characterised by an unfavourable clinical course with a more advanced disease stage, poor responsiveness to chemotherapy, short time to initiation of first treatment and shorter survival. In contrast, the CD38- negative group required minimal or no treatment, remained treatment-free for a longer time period and had prolonged survival (P < 0.05). CD38 expression was a robust marker in the majority of patients in that it was stable over time and not significantly influenced by chemotherapy. In conclusion, our data confirm recent studies suggesting a role of CD38 as a predictor of clinical outcome in patients with B-CLL.

Introduction

B cell chronic lymphocytic leukaemia is a heterogenous disease with a highly variable clinical course. Staging systems devised by Rai et al1 and Binet et al2 are useful methods for predicting survival and treatment requirements in patients with CLL. However, these staging systems are of limited prognostic value in early stages of the disease (Binet A or Rai stage 0 to 2), which include most of the patients at diagnosis.3,4 Therefore, a number of studies have focused on identifying novel prognostic markers, which may help define patient subgroups with favourable vs poor clinical outcome in early CLL.5,6 Recently, two independent studies by Damle et al7 and Hamblin et al8 have demonstrated that B-CLL may arise from either an immature pregerminal centre B cell with unmutated immunoglobulin (Ig) variable heavy chain (VH) genes or from a more mature post-germinal-centre B cell with somatically mutated Ig VH genes. Moreover, Damle et al7 found a strong correlation between the Ig VH gene mutation status, CD38 surface expression of the respective B-CLL clone and clinical outcome in individual patients. B-CLL cases with mutated Ig VH genes and low numbers of CD38-positive cells exhibit a favourable clinical course, while B-CLL patients with unmutated Ig VH genes are characterised by a poor outcome in terms of reduced survival and responsiveness to chemotherapy. However, in a follow-up study no association between CD38 expression and Ig VH gene mutation status was found, although the independent prognostic impact of both Ig VH gene mutation and CD38 positivity was confirmed.9 By contrast, Thunberg et al10 could not find any prognostic significance of CD38 expression in their CLL patient cohort.

CD38 is a single-chain type II transmembrane glycoprotein that is expressed by a variety of haematologic cells in an activation- and differentiation-dependent manner.11 Its cellular functions include a complex ectoenzymatic activity and the ability to transduce signals involved in the regulation of cell proliferation and survival.12 Furthermore, it mediates a selectin-like binding to endothelial cells, thus functioning as an adhesion molecule.13 In normal human B cell development, CD38 exhibits a discontinuous expression pattern, where the molecule is detected at high levels in B cell precursors, germinal centre and plasma cells, while circulating peripheral blood and tonsillar B cells have markedly lower CD38 surface expression.12 The potential role of CD38 in CLL pathophysiology is presently unknown. However, it is tempting to speculate that differences in CD38–ligand interaction between CLL clones may influence their proliferative behaviour and chance of survival.

Unlike analysis of the Ig VH gene mutation status, flow cytometric detection of CD38, expression can be conveniently performed in most clinical laboratories and may prove a valuable adjunct in the current staging system for predicting the clinical outcome in B-CLL patients. To explore this possibility further, we studied CD38 expression in 133 B-CLL patients and correlated the results with clinical and laboratory parameters.

Materials and methods

Patients

Between May 1994 and December 2000, 133 consecutive patients with chronic lymphocytic leukaemia from a single institution were enrolled in this study and analysed for several biological and clinical characteristics: age, sex, Binet stage, white blood cell count, haemoglobin level, platelet count, lactate dehydrogenase, thymidine kinase, immunoglobulin A (IgA) serum-concentration, survival, treatment history and time from diagnosis to first treatment. In each patient morphologic diagnosis of B-CLL was confirmed flow cytometrically14 revealing a typical CD19,20,5,23-positive Ig light chain, (κ or λ light chain) restricted immunophenotype. Patient characteristics are shown in Table 1. The mean follow-up time was 64.3 months (range 0–299).

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Cell surface staining and flow cytometry

Fresh heparinised peripheral blood (PB, n = 91) and bone marrow (BM, n = 42) samples were prepared for flow cytometry by ammonium chloride erythrocyte lysis (Ortho-mune Lysing Reagent; Ortho Diagnostic Systems, Raritan, NJ, USA). The immunophenotype was characterised using the following panel of fluorochrome-labeled monoclonal antibodies employing a standard three-colour flow cytometry approach (Figure 1):14 CD45-fluorescein isothiocyanate (FITC)/CD14-phycoerythrin (PE)/CD20-peridinin chlorophyll (PerCP); CD4 (FITC)/CD8 (PE)/CD3 (PerCP); κ light chain (FITC)/CD19 (PE)/CD5-phycoerythrin-cyanin (PeCy5); λ light chain (FITC)/CD19 (PE)/CD5 (PeCy5); IgM (FITC)/CD23 (PE)/CD19 (PECy5); CD10 (FITC)/CD38 (PE)/CD19 (PECy5). Antibodies were purchased from DAKO (Glostrup, Denmark; CD19, CD10, IgM, κ and λ light chains), Immunotech (Marseille, France; CD5) and Becton Dickinson (Heidelberg, Germany; CD38, CD4, CD8, CD3). Negative isotype-matched controls (Becton Dickinson) were used to define the threshold line separating surface marker positive and negative cells such that less than 1% of isotype-positive cells were present to the right of the line (Figure 1). A CLL population was considered CD38-positive when more than 20% of the gated population (CD19+/CD5+ cells) expressed it. To minimize potential contamination with coexisting normal B cells, only B-CLL cases in which >90% of CD19+ cells co-expressed CD5 were included in the study (Figure 1). In all experiments, a minimum of 10000 cells was analysed. The flow cytometer (FACScan; Becton Dickinson) was calibrated with CAliBRITE-3 beads (Becton Dickinson) and FACSComp Software (Becton Dickinson). Data acquisition and analysis was performed using Attractors and CellQuest software (Becton Dickinson). The same method of sample preparation and three-colour staining was used throughout the entire study period.

Representative flow cytometry dot plot analyses of CD38 expression in patients with B-CLL. Three-colour flow cytometry as detailed in Materials and methods was used to analyse CD38 surface expression on lymphocyte/monocyte gated CD19+ B cells co-expressing CD5. (a) Sample of a patient positive for CD38 (20% or more). (b) Sample of a patient negative for CD38 (less than 20%). Numbers are percentages of CD19+ B CLL cells expressing CD38.

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Statistical analysis

Survival times and censored waiting times measured from the time of diagnosis were plotted by the Kaplan–Meier method and compared using the log-rank test. Comparison of clinical and laboratory parameters between the CD38-positive and CD38-negative subgroups was performed using the Mann–Whitney U test (for quantitative variables) and chi-square test (for categorial variables). The Cox proportional model was used for multivariate analyses on overall survival. Significance was defined as P = 0.05, as determined by the two-tailed test.

Results

CD38 expression in B-CLL

We evaluated the surface expression of CD38 in 133 cases of B-CLL employing a three-colour flow cytometry approach with directly conjugated monoclonal antibodies (Figure 1). As per current convention, a given leukaemic population was considered positive for CD38 when ⩾20% of the B-CLL cells expressed the membrane marker.15,16Figure 2 shows the distribution of CD38 in the whole patient cohort. Based on the 20% cut-off value, 56 patients (42%) were defined as CD38-positive and 77 patients (58%) as CD38-negative, respectively.

Distribution of CD38 expression in the B-CLL study population (n = 133). CD38 expression was analysed employing a multicolour flow cytometry assay as described in Materials and methods. The dotted vertical line represents the 20% cut-off used to separate CD38-negative from CD38-positive patients. Data are percentages of CD38+/CD19+ B-CLL cells co-expressing CD5.

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Twenty-seven patients (13 CD38+ and 14 CD38 patients) were studied at two or more time-points (range 2 to 4). As illustrated in Figure 3, CD38 expression in individual patients was relatively stable over time and not substantially influenced by chemotherapy (five patients of the CD38 and 10 patients of the CD38+ subgroup received chemotherapy in the observation period) in the majority of patients analysed. Variations in CD38 staining over time were particularly high in CLL cases with CD38 levels around 50%. However, in none of the cases studied did we observe a cross-over of a CD38-negative patient to the CD38-positive cohort and vice versa (Figure 3).

CD38 expression in B-CLL over time. Twenty-seven patients were flow-cytometrically analysed for CD38 expression at two or more time-points (range 2 to 4). Each line in the graph represents an individual patient.

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In eight CLL patients, comparative analysis of CD38 in bone marrow and peripheral blood samples obtained at identical time-points yielded comparable results (Table 2) in both groups, suggesting that CD38 expression levels on B-CLL cells may be largely independent of the surrounding cellular microenvironment.

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Correlation of CD38 expression with clinical and laboratory data

The treatment histories of CD38+ and CD38 patients differed significantly (Table 3) in that the former group required more intensive chemotherapy over longer time periods than CD38 patients (P = 0.004). The higher treatment intensity in CD38+ patients correlated with a more advanced disease stage observed, both at diagnosis and study enrollment (Table 1). Furthermore, we found highly significant differences in disease progression as indicated by the treatment-free interval (Figure 4). The mean treatment-free interval (Table 1) was longer in the CD38 group (120 months) than in the CD38+ patient cohort (32 months, P = 0.00008). Finally, we compared overall survival among the two groups and again, observed statistically highly significant differences (Figure 5). The median survival of patients in the CD38+ cohort was 121 months, whereas the median survival for the CD38 group was not reached for the duration of follow-up (P = 0.00655).

Full size table

Probability of disease progression, as indicated by the treatment-free interval. Kaplan–Meier plot comparing time periods from diagnosis to initiation of chemotherapy in CD38-positive to CD38-negative CLL patients. Mean time from diagnosis to first treatment (months) was 120 vs 32 months in the CD38-negative and CD38-positive group, respectively. Statistical analysis was performed using the log-rank test.

Full size image

Overall survival in CD38-negative and CD38-positive B-CLL patients. Kaplan–Meier plot comparing survival based on CD38 expression. The mean survival of patients in the CD38+ cohort was 121 months, whereas the median survival for the CD38 group was not reached for the duration of follow-up. Statistical analysis was performed using the log-rank test.

Full size image

A comparison of further clinical and laboratory parameters among the two groups is shown in Table 1. Notably, significant differences were found for Binet stage, white blood cell count, platelet count, lactate dehydrogenase, β2- microglobulin and bone marrow histology (P < 0.05).

Univariate analysis of risk factors

Univariate Cox regression analysis was used to assess associations between survival time and potential risk factors. Binet stage (during follow-up), haemoglobin levels, platelet counts and CD38 expression and IgA serum concentration were identified as significant factors influencing survival (Table 4).

Full size table

Multivariate analysis

The following patient characteristics found to impact significantly on survival in the univariate analysis were included in the Cox regression model (complete case analysis, n = 102): CD38, Binet stage (during follow-up), platelet count, haemoglobin and IgA (Table 5). In multivariate analysis platelet count, haemoglobin and IgA, but not CD38 and Binet stage influenced overall survival.

Full size table

Discussion

This retrospective study was performed to evaluate the potential of CD38 expression as a prognostic indicator in B-CLL. In line with previous data,7 our results demonstrate that in the majority of patients the proportion of CLL cells co-expressing CD38 as determined by standard three-colour flow cytometry is relatively stable over time and does not appear to be influenced by chemotherapy. However, in a small subset of patients characterised by CD38 expression levels around 50%, we observed substantial variations in CD38 surface immunoreactivity in sequential samples obtained at different time-points. This finding may be due to technical problems encountered in the gating procedure used to define CD38 expression levels, ie small ‘random’ deviations in cursor positioning impact more profoundly on CLL populations with intermediate CD38 expression than on leukaemic populations with either high or low CD38 expression levels. However, due to the comparably small number of patients analysed in this subset of experiments, we cannot exclude the possibility that the observed differences indeed reflect fluctuations in CD38 expression in a minority of patients. Furthermore, intraindividual comparisons of specimens obtained simultaneously from peripheral blood and bone marrow yielded similar results. Taken together, these observations suggest that CD38 may be a robust marker that could be used reliably in most routine flow cytometry laboratories. Clearly, these data need to be confirmed in a larger patient cohort.

More importantly, we found that CLL cases displaying a high percentage of CD38 (⩾20%) are characterised by an unfavourable clinical course as compared with the CD38 negative patients (CD38 <20%). In particular, our data show significant differences in terms of overall survival and treatment requirements between the two groups confirming the work of Damle et al7 and Hamblin and colleagues9 and extending it to a larger patient cohort. Furthermore, the time from diagnosis to initiation of chemotherapy, used as a surrogate marker for progression-free survival,17 was significantly reduced in the CD38-positive, as compared to the CD38-negative patient cohort.

These findings contrast those of a recent report proposing that CD38 is a poor predictor of prognosis in CLL.10 This discrepancy may be at least partly explained by technical differences between the studies, ie the latter authors used a two-colour rather than a three colour flow cytometric assay and thus may have included normal residual B cells in their analysis, also the patient number evaluated for CD38 (n = 44) was relatively small.

The CD38 cut-off level employed for risk stratification in CLL patients remains a matter of controversy.10 In the initial study published by Damle et al7 a 30% cut-off value was chosen empirically based on a plot of CD38 expression vs Ig VH gene mutation status. Unmutated cases were found to exhibit a higher percentage of CD38 expression than mutated (post-germinal centre) B-CLL clones. However, while the prognostic significance of CD38 expression has been confirmed in two follow-up studies9,18 and now by the data presented here, the association between CD38 expression and Ig VH gene mutation remains conjectural.7,9,10 Thus, with the current state of knowledge, Ig VH gene mutation status and CD38 expression appear to be independent prognostic factors in B-CLL. The 20% CD38 cut-off value used in the present report was selected by reference to previously published immunophenotyping studies of haematologic malignancies and the recent proposals of the EGIL group.15,16 To better compare our data with those of previous studies7,9,18 survival analyses were recalculated using the 30% cut-off value employed by other authors.7,9,18 Interestingly, the resulting survival curves did not differ significantly from those previously obtained with the 20% cut-off value (data not shown). Furthermore, the median survival of our CD38-positive group (121 months) was very similar to that reported by Damle et al7 (120 months) and Hamblin and colleagues9 (105 months).

In conclusion, our data confirm previous studies showing that CD38 expression is a novel prognostic marker in B-CLL. It will be important to determine whether this parameter in conjunction with other established prognostic factors can improve risk stratification in the routine diagnostic work-up of CLL patients.

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Acknowledgements

This work represents a part of MNs MD thesis. We are indebted to numerous colleagues for generously contributing information on the clinical course and treatment histories of the study patients.

Author information

Affiliations

  1. Department of Haematology, Medical Faculty, University of Essen, Essen, Germany

    J Dürig, M Naschar, U Schmücker, A Hüttmann & U Dührsen

  2. Institute of Medical Informatics, Biometry and Epidemiology, Medical Faculty, University of Essen, Essen, Germany

    K Renzing-Köhler & T Hölter

Corresponding author

Correspondence to J Dürig.

About this article

Cite this article

Dürig, J., Naschar, M., Schmücker, U. et al. CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia. Leukemia16, 30–35 (2002). https://doi.org/10.1038/sj.leu.2402339

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Keywords

  • B-CLL
  • prognostic marker
  • CD38

Further reading

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    • , Laurie E. Littlepage
    •  & Basar Bilgicer

    Journal of Hematology & Oncology (2020)

  • Is Cd11c and Fmc7 Negativity in Chronic Lymphocytic Leukemia Poor Prognostic?

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    • , Sema Akinci
    • , Şule Mine Bakanay
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    •  & İmdat Dilek

    Indian Journal of Hematology and Blood Transfusion (2020)

  • Evaluation of CD38 expression in Sudanese patients with chronic lymphocytic leukemia

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  • Prognostic Factors in the Era of Targeted Therapies in CLL

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    Current Hematologic Malignancy Reports (2018)

  • Evaluation of Interleukin-9 Expression as a Potential Therapeutic Target in Chronic Lymphocytic Leukemia in a Cohort of Egyptian Patients

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Sours: https://www.nature.com/articles/2402339

Positive cd38

Cite this page: Bruehl F, Schürch CM. CD38. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cdmarkerscd38.html. Accessed October 17th, 2021.

Definition / general

  • Marker of cellular activation expressed by plasma cells, T cells, NK cells and other hematopoietic cell types during various stages of maturation

Essential features

  • Marker of activation and present on many hematopoietic cells, especially plasma cells
  • Used clinically as a prognostic marker in CLL as evaluated by flow cytometry
  • CD38 expression in lymphoid neoplasms is not specific for any discrete disease entity
  • Can be aberrantly expressed in carcinoma and melanoma
  • Absence of CD38 (in conjunction with CD34 positivity) is used as a marker for bone marrow hematopoietic stem cells

Interpretation

  • CD38 expression is considered positive when the cell membrane shows strong and diffuse staining; the cytoplasm and nucleus should not stain with CD38 (Blood 2008;111:5173)
  • Few studies have reported on the use and interpretation of anti-CD38 antibodies in tissue sections for diagnostic purposes; interpretation is difficult due to the prevalence of CD38 in many cell types and the necessity for quantitative assessment more amenable to flow cytometric studies (Am J Surg Pathol 2006;30:585)

Uses by pathologists

  • Flow cytometry is the primary use of anti-CD38 antibodies in the pathology laboratory
  • There is considerable confusion in the literature regarding CD38 and the unrelated antibody VS38 which targets the p63 antigen and is also used for detection of plasma cells in tissue sections and flow cytometry (Blood Cancer J 2018;8:117)

Prognostic factors

  • Chronic lymphocytic leukemia with CD38 expression is associated with a more aggressive clinical course and shorter overall survival (J Clin Pathol 2002;55:180, Br J Haematol 2003;120:1017)
  • Hairy cell leukemia with CD38 expression is associated with a more aggressive clinical course (Cancer Res 2015;75:3902)
  • Acute myeloid leukemia with CD38 expression was shown to be associated with a favorable prognosis and high numbers of immature CD34+ / CD38- blasts in myeloid leukemia are associated with unfavorable prognosis (Leuk Res 2000;24:153, Leukemia 2019;33:1102)
  • CD38 expression on multiple myeloma cells has been correlated to anti-CD38 treatment response (Blood 2016;128:959)
    • In the future, CD38 expression in tissue sections could be used to monitor anti-CD38 therapy with (bispecific) antibodies for early detection of treatment resistance (loss of CD38 expression)

Microscopic (histologic) description

  • Plasmacytoma: see images below

Microscopic (histologic) images


Contributed by Frido Bruehl, M.D.

Plasmacytoma

Plasmacytoma, CD38

Positive staining - normal

  • Plasma cells, hematopoietic progenitor cells, NK cells, B and T cells, monocytes and basophils (Chem Immunol 2000;75:169)
  • Neurons, small lymph vessels in intestinal tract and pancreatic islets, perivascular autonomic nerve terminals, double positive thymocytes, erythrocytes (Brain Res 1995;697:235, Virchows Arch 2002;441:605, J Biol Regul Homeost Agents 1998;12:81, Int Immunol 2003;15:1105, Hematology 2007;12:409)

Positive staining - disease

  • B cell lymphoid neoplasms:
  • T cell lymphoid neoplasms:
  • Myeloid neoplasms:
    • CD38 is heterogeneously expressed in acute myeloid leukemia (Haematologica 2019;104:e100)
    • CD38 positivity is used as an inclusion criterion in clinical trials evaluating anti-CD38 therapies
  • Other:

Negative staining

  • Absence of CD38 expression does not reliably exclude a given pathologic diagnosis based on currently available data
  • CD38 surface expression may be reduced on multiple myeloma / plasma cells due to CD38 internalization induced by treatment with anti-CD38 antibodies (e.g. daratumumab) (Oncoimmunology 2018;7:e1486948)
  • CD38 has been used in conjunction with CD117 in fluorescence activated cell sorting of mast cells from bone marrow samples (CD117 positive and CD38 negative cells) (Am J Pathol 1996;149:1493)

Flow cytometry images


Contributed by Frido Bruehl, M.D.

CD38 positive CLL

CD38 negative CLL

Plasma cell neoplasm, CD38 versus CD45

Plasma cell neoplasm, CD38 versus CD138

Plasma cell neoplasm, CD38 versus CD19

Sample pathology report

  • Bone lesion, needle core biopsy:
    • Monotypic kappa expressing plasma cell neoplasm, consistent with plasmacytoma (see comment)
    • Comment: The needle core biopsy demonstrates a dense infiltration by a clonal plasma cell population with kappa light chain restriction. The neoplastic plasma cells are positive for CD38, CD138 and CD79a. Lambda light chains, CD20 and CD43 are not expressed. There are only scattered CD3 positive T cells. There is no amyloid deposition. In summary, the bone lesions represents a plasmacytoma; clinical, serological and imaging correlation is required.

Board review style question #1


Which of the following immunohistochemical markers has the lowest sensitivity for plasma cell neoplasms?

  1. CD38
  2. CD138
  3. CD20
  4. IgM
  5. VS38c

Board review style answer #1

D. IgM is the best answer. IgM secreting plasma cell neoplasms are exceedingly rare, meanwhile CD20 is expressed in up to 20% of plasma cell neoplasms (Am J Hematol 2010;85:853).

Comment Here

Reference: CD38

Back to topSours: https://www.ncbi.nlm.nih.gov/pubmed/" target="_blank
CD38: a promising target for multiple myeloma antibody therapy

CD38

CD38
Protein CD38 PDB 1yh3.png
Available structures
PDBOrtholog search: PDBeRCSB
List of PDB id codes

4TMF, 1YH3, 1ZVM, 2EF1, 2HCT, 2I65, 2I66, 2I67, 2O3Q, 2O3R, 2O3S, 2O3T, 2O3U, 2PGJ, 2PGL, 3DZF, 3DZG, 3DZH, 3DZI, 3DZJ, 3DZK, 3F6Y, 3I9M, 3I9N, 3OFS, 3RAJ, 3ROK, 3ROM, 3ROP, 3ROQ, 3U4H, 3U4I, 4CMH, 4F45, 4F46, 4OGW, 4XJS, 4XJT, 5F1K, 5F1O, 5F21

Identifiers
AliasesCD38, ADPRC1, ADPRC 1, CD38 molecule
External IDsOMIM: 107270MGI: 107474HomoloGene: 1345GeneCards: CD38
EC number2.4.99.20
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)Chr 4: 15.78 – 15.85 MbChr 5: 43.87 – 43.91 Mb
PubMed search[3][4]
Wikidata

CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein[5] found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling.[6]

In humans, the CD38 protein is encoded by the CD38 gene which is located on chromosome 4.[7][8] CD38 is a paralog of CD157, which is also located on chromosome 4 (4p15) in humans.[9]

History and tissue distribution[edit]

CD38 was first identified in 1980 as a surface marker (cluster of differentiation) of thymus celllymphocytes.[10][11] In 1992 it was additionally described as a surface marker on B cells, monocytes, and natural killer cells (NK cells).[10] About the same time, CD38 was discovered to be not simply a marker of cell types, but an activator of B cells and T cells.[10] In 1992 the enzymatic activity of CD38 was discovered, having the capacity to synthesize the calcium-releasing second messengerscyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP).[10]

CD38 is most frequently found on plasma B cells, followed by natural killer cells, followed by B cells and T cells, and then followed by a variety of cell types.[12]

Function[edit]

CD38 can function either as a receptor or as an enzyme.[13] As a receptor, CD38 can attach to CD31 on the surface of T cells, thereby activating those cells to produce a variety of cytokines.[13]

CD38 is a multifunctional enzyme that catalyzes the synthesis of ADP ribose (ADPR) (97%) and cyclic ADP-ribose (cADPR) (3%) from NAD+.[14][15] CD38 is thought to be a major regulator of NAD+ levels, its NADase activity is much higher than its function as an ADP-rybosyl-cyclase: for every 100 molecules of NAD+ converted to ADP ribose it generates one molecule of cADPR.[16][14] When nicotinic acid is present under acidic conditions, CD38 can hydrolyze nicotinamide adenine dinucleotide phosphate (NADP+) to NAADP.[14][17]

These reaction products are essential for the regulation of intracellular Ca2+.[18] CD38 occurs not only as an ectoezyme on cell outer surfaces, but also occurs on the inner surface of cell membranes, facing the cytosol performing the same enzymatic functions.[19]

CD38 is believed to control or influence neurotransmitter release in the brain by producing cADPR.[20] CD38 within the brain enables release of the affiliative neuropeptideoxytocin.[21]

Like CD38, CD157 is a member of the ADP-ribosyl cyclase family of enzymes that catalyze the formation of cADPR from NAD+, although CD157 is a much weaker catalyst than CD38.[22] The SARM1 enzyme also catalyzes the formation of cADPR from NAD+,[19] but SARM1 elevates cADPR much more efficiently than CD38.[23]

Clinical significance[edit]

The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism.[18][24]

CD31 on endothelial cells binds to the CD38 receptor on natural killer cells for those cells to attach to the endothelium.[25][26] CD38 on leukocytes attaching to CD16 on endothelial cells allows for leukocyte binding to blood vessel walls, and the passage of leukocytes through blood vessel walls.[9]

The cytokine interferon gamma and the Gram negative bacterial cell wall component lipopolysaccharide induce CD38 expression on macrophages.[26] Interferon gamma strongly induces CD38 expression on monocytes.[18] The cytokine tumor necrosis factor strongly induces CD38 on airway smooth muscle cells inducing cADPR-mediated Ca2+, thereby increasing dysfunctional contractility resulting in asthma.[27]

The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas,[28] solid tumors, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions.

CD38 increases airway contractility hyperresponsiveness, is increased in the lungs of asthmatic patients, and amplifies the inflammatory response of airway smooth muscle of those patients.[15]

Increased expression of CD38 is an unfavourable diagnostic marker in chronic lymphocytic leukemia and is associated with increased disease progression.[29]

Clinical application[edit]

CD38 inhibitors may be used as therapeutics for the treatment of asthma.[30]

CD38 has been used as a prognostic marker in leukemia.[31]

Daratumumab (Darzalex) which targets CD38 has been used in treating multiple myeloma.[32][33]

The use of Daratumumab can interfere with pre-blood transfusion tests, as CD38 is weakly expressed on the surface of erythrocytes. Thus, a screening assay for irregular antibodies against red blood cell antigens or a direct immunoglobulin test can produce false-positive results.[34] This can be sidelined by either pretreatment of the erythrocytes with dithiothreitol (DTT) or by using an anti-CD38 antibody neutralizing agent, e.g. DaraEx.

Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are NAD+ precursors, but when NR or NMN are administered, CD38 can degrade these precursors before they can enter cells.[35]

Inhibitors[edit]

Aging studies[edit]

A gradual increase in CD38 has been implicated in the decline of NAD+ with age.[45][46] Treatment of old mice with a specific CD38 inhibitor, 78c, prevents age-related NAD+ decline.[47] CD38 knockout mice have twice the levels of NAD+ and are resistant to age-associated NAD+ decline,[35] with dramatically increased NAD+ levels in major organs (liver, muscle, brain, and heart).[48] On the other hand, mice overexpressing CD38 exhibit reduced NAD+ and mitochondrial dysfunction.[35]

Macrophages are believed to be primarily responsible for the age-related increase in CD38 expression and NAD+ decline.[49] Macrophages accumulate in visceral fat and other tissues with age, leading to chronic inflammation.[50]Secretions from senescent cells induce high levels of expression of CD38 on macrophages, which becomes the major cause of NAD+ depletion with age.[51]

Decline of NAD+ in the brain with age may be due to increased CD38 on astrocytes and microglia, leading to neuroinflammation and neurodegeneration.[20]

References[edit]

  1. ^ abcGRCh38: Ensembl release 89: ENSG00000004468 - Ensembl, May 2017
  2. ^ abcGRCm38: Ensembl release 89: ENSMUSG00000029084 - Ensembl, May 2017
  3. ^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^Orciani M, Trubiani O, Guarnieri S, Ferrero E, Di Primio R (October 2008). "CD38 is constitutively expressed in the nucleus of human hematopoietic cells". Journal of Cellular Biochemistry. 105 (3): 905–12. doi:10.1002/jcb.21887. PMID 18759251. S2CID 44430455.
  6. ^"Entrez Gene: CD38 CD38 molecule".
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  8. ^Nata K, Takamura T, Karasawa T, Kumagai T, Hashioka W, Tohgo A, Yonekura H, Takasawa S, Nakamura S, Okamoto H (February 1997). "Human gene encoding CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase): organization, nucleotide sequence and alternative splicing". Gene. 186 (2): 285–92. doi:10.1016/S0378-1119(96)00723-8. PMID 9074508.
  9. ^ abQuarona V, Zaccarello G, Chillemi A (2013). "CD38 and CD157: a long journey from activation markers to multifunctional molecules". Cytometry Part B. 84 (4): 207–217. doi:10.1002/cyto.b.21092. PMID 23576305. S2CID 205732787.
  10. ^ abcdLee, H.C., ed. (2002). A Natural History of the Human CD38 Gene. In:Cyclic ADP-Ribose and NAADP. Springer Publishing. doi:10.1007/978-1-4615-0269-2_4. ISBN .
  11. ^Reinherz EL, Kung PC, Schlossman SF (1980). "Discrete stages of human intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage". Proceedings of the National Academy of Sciences of the United States of America. 77 (3): 1588–1592. Bibcode:1980PNAS...77.1588R. doi:10.1073/pnas.77.3.1588. PMC 348542. PMID 6966400.
  12. ^van de Donk N, Richardson PG, Malavasi F (2018). "CD38 antibodies in multiple myeloma: back to the future". Blood. 131 (1): 13–29. doi:10.1182/blood-2017-06-740944. PMID 29118010.
  13. ^ abNooka AK, Kaufman JL, Hofmeister CC, Joseph NS (2019). "Daratumumab in multiple myeloma". Cancer. 125 (14): 2364–2382. doi:10.1002/cncr.32065. PMID 30951198. S2CID 96435958.
  14. ^ abcKar A, Mehrotra S, Chatterjee S (2020). "CD38: T Cell Immuno-Metabolic Modulator". Cells. 9 (7): 1716. doi:10.3390/cells9071716. PMC 7408359. PMID 32709019.
  15. ^ abGuedes A, Dileepan M, Jude JA, Kannan MS (2020). "Role of CD38/cADPR signaling in obstructive pulmonary diseases". Current Opinion in Pharmacology. 51: 29–33. doi:10.1016/j.coph.2020.04.007. PMC 7529733. PMID 32480246.
  16. ^Braidy N, Berg J, Clement J, Sachdev P (2019). "Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes". Antioxidants & Redox Signaling. 10 (2): 251–294. doi:10.1089/ars.2017.7269. PMC 6277084. PMID 29634344.
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Further reading[edit]

  • States DJ, Walseth TF, Lee HC (December 1992). "Similarities in amino acid sequences of Aplysia ADP-ribosyl cyclase and human lymphocyte antigen CD38". Trends in Biochemical Sciences. 17 (12): 495. doi:10.1016/0968-0004(92)90337-9. PMID 1471258.
  • Malavasi F, Funaro A, Roggero S, Horenstein A, Calosso L, Mehta K (March 1994). "Human CD38: a glycoprotein in search of a function". Immunology Today. 15 (3): 95–7. doi:10.1016/0167-5699(94)90148-1. PMID 8172650.
  • Guse AH (May 1999). "Cyclic ADP-ribose: a novel Ca2+-mobilising second messenger". Cellular Signalling. 11 (5): 309–16. doi:10.1016/S0898-6568(99)00004-2. PMID 10376802.
  • Funaro A, Malavasi F (1999). "Human CD38, a surface receptor, an enzyme, an adhesion molecule and not a simple marker". Journal of Biological Regulators and Homeostatic Agents. 13 (1): 54–61. PMID 10432444.
  • Mallone R, Perin PC (2006). "Anti-CD38 autoantibodies in type? diabetes". Diabetes/Metabolism Research and Reviews. 22 (4): 284–94. doi:10.1002/dmrr.626. PMC 2763400. PMID 16544364.
  • Partidá-Sánchez S, Rivero-Nava L, Shi G, Lund FE (2007). "CD38: an ecto-enzyme at the crossroads of innate and adaptive immune responses". Crossroads between Innate and Adaptive Immunity. Advances in Experimental Medicine and Biology. 590. pp. 171–83. doi:10.1007/978-0-387-34814-8_12. ISBN . PMID 17191385.
  • Jackson DG, Bell JI (April 1990). "Isolation of a cDNA encoding the human CD38 (T10) molecule, a cell surface glycoprotein with an unusual discontinuous pattern of expression during lymphocyte differentiation". Journal of Immunology. 144 (7): 2811–5. PMID 2319135.
  • Dianzani U, Bragardo M, Buonfiglio D, Redoglia V, Funaro A, Portoles P, Rojo J, Malavasi F, Pileri A (May 1995). "Modulation of CD4 lateral interaction with lymphocyte surface molecules induced by HIV-1 gp120". European Journal of Immunology. 25 (5): 1306–11. doi:10.1002/eji.1830250526. PMID 7539755. S2CID 37717142.
  • Nakagawara K, Mori M, Takasawa S, Nata K, Takamura T, Berlova A, Tohgo A, Karasawa T, Yonekura H, Takeuchi T (1995). "Assignment of CD38, the gene encoding human leukocyte antigen CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase), to chromosome 4p15". Cytogenetics and Cell Genetics. 69 (1–2): 38–9. doi:10.1159/000133933. PMID 7835083.
  • Tohgo A, Takasawa S, Noguchi N, Koguma T, Nata K, Sugimoto T, Furuya Y, Yonekura H, Okamoto H (November 1994). "Essential cysteine residues for cyclic ADP-ribose synthesis and hydrolysis by CD38". The Journal of Biological Chemistry. 269 (46): 28555–7. doi:10.1016/S0021-9258(19)61940-X. PMID 7961800.
  • Takasawa S, Tohgo A, Noguchi N, Koguma T, Nata K, Sugimoto T, Yonekura H, Okamoto H (December 1993). "Synthesis and hydrolysis of cyclic ADP-ribose by human leukocyte antigen CD38 and inhibition of the hydrolysis by ATP". The Journal of Biological Chemistry. 268 (35): 26052–4. doi:10.1016/S0021-9258(19)74275-6. PMID 8253715.
  • Nata K, Takamura T, Karasawa T, Kumagai T, Hashioka W, Tohgo A, Yonekura H, Takasawa S, Nakamura S, Okamoto H (February 1997). "Human gene encoding CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase): organization, nucleotide sequence and alternative splicing". Gene. 186 (2): 285–92. doi:10.1016/S0378-1119(96)00723-8. PMID 9074508.
  • Feito MJ, Bragardo M, Buonfiglio D, Bonissoni S, Bottarel F, Malavasi F, Dianzani U (August 1997). "gp 120s derived from four syncytium-inducing HIV-1 strains induce different patterns of CD4 association with lymphocyte surface molecules". International Immunology. 9 (8): 1141–7. doi:10.1093/intimm/9.8.1141. PMID 9263011.
  • Ferrero E, Malavasi F (October 1997). "Human CD38, a leukocyte receptor and ectoenzyme, is a member of a novel eukaryotic gene family of nicotinamide adenine dinucleotide+-converting enzymes: extensive structural homology with the genes for murine bone marrow stromal cell antigen 1 and aplysian ADP-ribosyl cyclase". Journal of Immunology. 159 (8): 3858–65. PMID 9378973.
  • Deaglio S, Morra M, Mallone R, Ausiello CM, Prager E, Garbarino G, Dianzani U, Stockinger H, Malavasi F (January 1998). "Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member". Journal of Immunology. 160 (1): 395–402. PMID 9551996.
  • Yagui K, Shimada F, Mimura M, Hashimoto N, Suzuki Y, Tokuyama Y, Nata K, Tohgo A, Ikehata F, Takasawa S, Okamoto H, Makino H, Saito Y, Kanatsuka A (September 1998). "A missense mutation in the CD38 gene, a novel factor for insulin secretion: association with Type II diabetes mellitus in Japanese subjects and evidence of abnormal function when expressed in vitro". Diabetologia. 41 (9): 1024–8. doi:10.1007/s001250051026. PMID 9754820.

External links[edit]

PDB gallery

  • 1yh3: Crystal structure of human CD38 extracellular domain

  • 1zvm: Crystal structure of human CD38: cyclic-ADP-ribosyl synthetase/NAD+ glycohydrolase

  • 2ef1: Crystal structure of the extracellular domain of human CD38

  • 2hct: Acidic residues at the active sites of CD38 and ADP-ribosyl cyclase determine NAAPD synthesis and hydrolysis activities

  • 2i65: Structural Basis for the Mechanistic Understanding Human CD38 Controlled Multiple Catalysis

  • 2i66: Structural Basis for the Mechanistic Understanding Human CD38 Controlled Multiple Catalysis

  • 2i67: Structural Basis for the Mechanistic Understanding Human CD38 Controlled Multiple Catalysis

  • 2o3q: Structural Basis for Formation and Hydrolysis of Calcium Messenger Cyclic ADP-ribose by Human CD38

  • 2o3r: Structural Basis for Formation and Hydrolysis of Calcium Messenger Cyclic ADP-ribose by Human CD38

  • 2o3s: Structural Basis for Formation and Hydrolysis of Calcium Messenger Cyclic ADP-ribose by Human CD38

  • 2o3t: Structural Basis for Formation and Hydrolysis of Calcium Messenger Cyclic ADP-ribose by Human CD38

  • 2o3u: Structural Basis for Formation and Hydrolysis of Calcium Messenger Cyclic ADP-ribose by Human CD38

  • 2pgj: Catalysis associated conformational changes revealed by human cd38 complexed with a non-hydrolyzable substrate analog

  • 2pgl: Catalysis associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analog

Sours: https://en.wikipedia.org/wiki/CD38

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