CD38 (CD38 molecule)

2012-02-01   Silvia Deaglio , Tiziana Vaisitti 

Department of Genetics, Biology, Biochemistry, University of Turin, Turin, Italy




Atlas Image
Gene structure of CD38. Colored boxes represent the 8 exons; the total length, the starting and ending base pair of the gene are indicated.


The genomic DNA of CD38 extends for 71172 base pairs with 8 exons, starting at 15779898 bp and ending at 15851069 bp. The CD38 gene is located at 4p15.32. The 5-flanking promoter region of the gene contains a CpG island that is ~900 bp long and includes exon 1 and the 5-end of the intron 1. This region contains a binding site for the transcription factor Sp1 and several potential binding for other factors such as interleukins, interferon and hormones. A critical region in the CD38 gene is the retinoic acid responsive element (RARE) responsible for the upregulation of CD38 expression induced by all-trans retinoic acid (Nata et al., 1997; Ferrero and Malavasi, 1999). The 5-end of the intron 1 contains also a C→ G single nucleotide polymorphism (SNP), rs6449182, that leads to the presence or absence of a PvuII restriction site (see below). The SNP is located within a putative E-box, a region of binding of the E proteins with a consequent regulation of gene transcription. In the B cell compartment a relevant role is played by E2A, that controls the expression of several B lineage genes. E2A was demonstrated to bind to the E-box of the CD38 gene, regulating its expression, and the binding of the protein is influenced by the CD38 genotype, with the G allele resulting in a stronger binding of E2A (Saborit-Villarroya et al., 2011).


The mRNA of CD38 (NM_001775.2) contains 1494 bp.


Atlas Image
CD38 protein structure. CD38 is a transmembrane molecule of 300 aa. The intracellular (IC), the transmembrane (TM) and the extracellular domains are indicated in the diagram. The different portions of the aminoacidic chain are shown as coded by the different exons.


Human CD38 is made up of a single chain of 300 aa with a corresponding molecular weight of approximately 45 kDa. It is characterized by a short cytoplasmic tail (21 aa), a small transmembrane domain (23 aa) and a large extracellular domain (256 aa). CD38 is a glycoprotein comprising 2 to 4 N-linked oligosaccharide chains containing sialic acid residues. The overall structure of the CD38 molecule is stabilized by six pairs of disulphide bonds.
Besides the monomeric membrane-bound form of CD38, a soluble form of CD38 of approximately 78 kDa (p78) (Mallone et al., 1998) and a high-molecular weight form of 190 kDa (p190) (Umar et al., 1996), have been described. The latter fits with a tetrameric conformation of the molecule, both displaying enzymatic activities.
The carboxyl-terminal of the molecule harbors the catalytic site (CD38 is defined as an ecto-enzyme) and the binding site for CD31, the non-substrate CD38 ligand (Deaglio et al., 1998).
The overall structure of the CD38 molecule, obtained by crystallographic analyses, is "L"-shaped and can be divided into two separate domains. The N-terminal domain, formed by a bundle of α helices (α1, α2, α3, α5, α6) and two short β strands (β1, β3), and the C-terminal domain, formed by four-stranded parallel β sheet (β2, β4, β5, and β6) surrounded by two long (α8 and α9) and two short α helices (α4 and α7). These two distinct domains are connected by a hinge region composed of three peptide chains. The enzymes overall topology is similar to the related proteins CD157 and the Aplysia ADP-ribosyl cyclase, with the exception of important structural changes at the two termini. The extended positively charged N terminus has lateral associations with the other CD38 molecule in the crystallographic asymmetric unit. The analysis of the CD38 substrate binding models revealed three key residues that may be critical in controlling CD38 enzimatic functions. Indeed, the positions of residues Glu226, Trp125, and Trp189, which are essential for the enzymes catalytic activity are highly conserved; Trp125 and Trp189 are suggested as the residues for recognizing and positioning the substrate by hydrophobic interactions, while Glu226 is the catalytic residue that takes part in the formation of the catalytic intermediate) (Munshi et al., 2000; Liu et al., 2005).


Human CD38 is surface expressed by various cells of both hematopoietic and non-hematopoietic lineages. In the T cell compartment, CD38 is expressed by a significant fraction of human thymocytes, mainly at the double-positive stage. In B cells, the expression is tightly regulated during cell ontogenesis, being present at high levels in bone marrow precursors and in terminally differentiated plasma cells. CD38 is expressed also in circulating monocytes, but not in resident macrophages, and in circulating and residential NK cells and granulocytes.
CD38 is also present in many tissues other than haematopoietic cells, including normal prostatic epithelial cells, pancreatic islet cells and the brain, where it is detected in perikarya and dendrites of many neurons, such as the cerebellar Purkinje cells, in rat astrocytes and in perivascular autonomic nerve terminals. Other CD38+ cells include smooth and striated muscle cells, renal tubules, retinal gangliar cells and cornea (Malavasi et al., 2008).


CD38 is a type II transmembrane protein expressed on plasma and nuclear membranes.


CD38 is a multifunctional ecto-enzyme involved in signal transduction, cell adhesion and calcium signaling. The binding to the ligand CD31, initiates a signaling cascade that includes phosphorylation of sequential intracellular targets and increases cytoplasmic Ca2+ levels, mediating different biological events depending on the cells type (e.g., activation, proliferation, apoptosis, cytokines secretion and homing). As an enzyme, CD38 metabolizes NAD+/NADP+, generating cADPR, ADP-ribose and NAADP (Lee, 2006). These products bind different receptors and channels (IP3 receptors IP3R, Ryanodine receptor RyR and Transient receptor potential cation channel subfamily M member 2 TRPM2) and are involved in the regulation of intracellular Ca2+ and activation of critical signaling pathways connected to the control of cell metabolism, genomic stability, apoptosis, cell signaling, inflammatory response and stress tolerance (Guse, 2005).


The CD38 gene is conserved in human, chimpanzee, dog, mouse, rat and chicken. Human CD38 shares a 25-30% homology in amino acid sequence to the Aplysia ADP ribosyl cyclase and it is highly homologous to CD157 (BST-1), originated by gene duplication (Ferrero and Malavasi, 1997; Ferrero and Malavasi, 1999).



Not yet reported.

Implicated in

Entity name
Chronic lymphocytic leukemia (CLL)
CLL is the most common adult leukemia in the United States and Europe that results from the accumulation of small B lymphocytes expressing CD19/CD5/CD23 in blood, bone marrow, lymph nodes and other lymphoid tissues (Chiorazzi and Ferrarini, 2003). The latter districts represent permissive niches where lymphocytes can proliferate in response to microenvironmental signals (Malavasi et al., 2011). The incidence rates in men are nearly twice as high as women and it is less common among people of African or Asian origin. Advanced age and a family history of leukemia and lymphoma are additional risk factors (Dores, 2007).
CLL is currently categorized into prognostic groups based on the clinical staging systems developed by Rai and Binet (Rai et al., 1975; Binet et al., 1981). The disease is heterogenous from the clinical point of view with at least three group of patients. Approximately one-third of CLL patients are affected by an indolent form of disease that does not require treatment. Another third of patients presents with a leukemia that will require iterative therapies, affecting their quality and length of life. A small fraction of CLL patients will develop Richter syndrome (RS), represented in most cases by diffuse large B-cell lymphoma (DLBCL) arising from the transformation of the original CLL clone. RS is a highly aggressive syndrome with a median overall survival of 5 to 8 months (Hallek et al., 2008). Several molecular markers have been identified with a prognostic significance to distinguish among the different groups of patients. The most credited molecular indicators are the absence of mutations in the IgVH genes and the expression of CD38 and Zap70 (Cramer and Hallek, 2011).
CLL is associated with chromosomal deletions and amplifications: the most frequent is trisomy of chromosome 12 (+12; 16%) and deletion of chromosomal regions 11q (18%), 17p (7%) and 13q14 (55%). The molecular consequence of trisomy 12 are unknown, but probably related to an elevated gene dosage of a proto-oncogene. Del(11)(q22-q23) comprise ataxia teleangectasia (ATM) gene, a gene related to genomic instability and DNA-repair and associated with a predisposition to lymphoid malignancies. The inability to repair DNA-damage due to ATM-deficiency contributes to CLL pathogenesis, allowing accumulation of additional genetic mutations during cellular proliferation. A similar pathogenetic mechanism occurs in CLL with del(17p13) that include the TP53 tumor suppressor gene. The del(13q14) mono- or bi-allelic involves two microRNAs, miR-15a and miR16-1, that can be two potential candidate tumor suppressor genes, even though their targets are still unknown (Klein and Dalla-Favera, 2010; Zenz et al., 2010).
In CLL, elevated expression of CD38 is associated with several adverse prognostic factors such as advanced disease stage, higher incidence of lymphadenopathy, high-risk cytogenetics, shorter lymphocytes doubling time (LDT), shorter time to initiation of first treatment (TFT) and poorer response to therapy. Besides being a prognostic marker, CD38 is a key element in the pathogenesis of CLL, as a component of a molecular network delivering growth and survival signals to CLL cells (Deaglio et al., 2005). CD38 performs as a receptor on leukemic cells following the binding to its ligand CD31 and the signals are mediated by Zap70, another negative prognosticator for the disease and a limiting factor for the activation of the CD38-mediated pathway (Deaglio et al., 2003; Deaglio et al., 2007). CD38 can work in association with chemokines and their receptors, mainly CXCL12/CXCR4, influencing the migratory responses and contributing to the recirculation of neoplastic cells from blood to lymphoid organs (Vaisitti et al., 2010) and with specific adhesion molecules, belonging to the integrin family (Zucchetto et al., 2009; Zucchetto et al., 2012). An important role in the oncogenesis of CLL is likely by the CD38 SNP (see above) that has been recently described as an independent risk factor for Richter syndrome (RS) transformation. The frequency of the G allele is significantly higher in a subset of CLL patients characterized by clinical and molecular markers of poor prognosis, with the highest allele frequency scored by patients with RS (Aydin, 2008). The same G allele was independently reported as a susceptibility factor for CLL development in a Polish population (Jamroziak et al., 2009). The presence of the rare G allele is not correlated to a higher expression of CD38 by CLL cells, but is responsible for the ability to modulate CD38 expression in response to environmental signals.
Entity name
Multiple myeloma is a malignancy of the immune system characterized by accumulation of plasma cells in the bone marrow (BM), by a high concentration of monoclonal Ig in serum or urine and lytic bone lesions arising from osteolytic activity of plasma cell-activated osteoclasts. The proliferation of plasma cells in MM may interfere with the normal production of blood cells, resulting in leukopenia, anemia and thrombocytopenia. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. It is diagnosed with blood tests, microscopic examination of the bone marrow (bone marrow biopsy) and radiographs of commonly involved bones.
MM is characterized by neoplastic proliferation of plasma cells involving more than 10% of the BM. Increasing evidence suggests than the BM microenvironment of tumor cells plays a pivotal role in the pathogenesis of myeloma. MM is a heterogenous disease, with survival ranging from 1 year to more than 10 years. The 5-year relative survival rate is around 40%. Survival is higher in younger people. The tumor burden (based on C-reactive protein CRP and beta-2-microglobulin β2m) and the proliferation rate are the two key indicators for the prognosis in patients with MM (Palumbo and Anderson, 2011).
MM is characterized by very complex cytogenetic and molecular genetic aberrations. The chromosome number is usually either hyperdiploid with multiple trisomies or hypodiploid with one of several types of immunoglobulin heavy chain (Ig) translocations. The chromosome status and Ig rearrangements are two genetic criteria to stratify patients into a specific prognostic group. The malignant cells of MM are the most mature cells of the B lineage. B cell maturation is associated with a programmed rearrangement of DNA sequence in the process encoding the structure of mature immunoglobulins. Indeed, MM is characterized by over-production of monoclonal immunoglobulin G (IgG), IgA and/or light chains. Rearrangements involving the switch regions of immunoglobulin heavy chain (IgH) gene at the 14q32 with various partner genes (t(4;14), t(14;16), t(11;14)) represent the most common structural abnormalities in MM. Several chromosomal aberrations are acquired during disease progression, involving MYC rearrangements, chromosome 13 (del(13q)), 17 (del(17p)) and 1p deletions. These chromosomal abnormalities are associated to specific oncogenes, such as c-myc that develop early in the course of plasma cell tumors, while changes in other oncogenes such as N-ras and K-ras are more often found in MM after BM relapse. Abnormalities are also described for tumor suppressor genes such as TP53, associated with spread to other organs. (Sawyer, 2011).
CD38 is predominantly expressed by BM precursor cells and terminally differentiated plasma cells. MM cells show moderate to high expression levels of CD38. The need for improved MM therapy has stimulated the development of monoclonal antibodies (mAbs) targeting either MM cells or cells of the BM microenvironment. CD38 is one of the candidates: recently, a human anti-CD38 (HuMax-CD38 or Daratunumab) antibody was generated and preclinical studies indicated that it is highly effective in killing primary CD38+CD138+ patients MM cells and a range of MM/lymphoid cell lines by both Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Moreover, in a SCID mouse animal model, this antibody inhibited CD38+ tumor cell growth (Stevenson et al., 2006; de Weers et al., 2011; Tai and Anderson, 2011). Another fully human anti-CD38 mAb (MorphoSysAG) was reported to efficiently trigger ADCC against CD38+ MM cell lines and patients MM cells in vitro as well as in vivo in a xenograft mouse model (Stevenson et al., 2006).
Entity name
Acute myelogenous leukemia (AML) is a cancer of the myeloid lineage, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells (maturational arrest of bone marrow cells in the earliest stages of development due to the activation of abnormal genes through chromosomal translocations and other genetic abnormalities).
AML has several subtypes: 5-year survival rates vary from 15% to 70% and relapse rates vary from 33 to 78% depending on subtype. The French-American-British (FAB) classification system divides AML into 8 subtypes, M0 through M7, based on the type of cell from which the leukemia developed and its degree of maturation (morphology of the neoplastic cells and cytogenetic analysis to characterize chromosomal abnormalities). The M3 subtype, also known as acute promyelocytic leukemia (APL), is caused by an arrest of leukocyte differentiation at the promyelocyte stage. Various clinical regimens combining anthracyclines, retinoic acid (RA), that induces APL differentiation, and arsenic trioxide, that triggers apoptosis and differentiation, results in a remission of 80-90% of patients (de Thé and Chen, 2010; Kamimura et al., 2011).
Cytogenetics is the single most important prognostic factor in AML. About 50% of AML patients have a normal cytogenetics; certain cytogenetic abnormalities are associated with good outcomes (t(15;17) in acute promyelocytic leukemia), while other cytogenetic abnormalities are associated with a poor prognosis and a high risk of relapse after treatment. APL is characterized by a reciprocal translocation, t(15;17), that results in a fusion oncogene, PML (promyelocytic leukemia)-RARα (retinoic acid receptor α) with a consequent block of the normal myeloid differentiation program and increased self-renewal of leukemic progenitors cells.
Retinoic acid (RA), the vitamin A derivative plays a critical role during the differentiation of myeloid progenitors towards the neutrophil lineage. This role is primarily mediated by binding of RA to RARalpha (RARα , a nuclear receptor that modulates the expression of multiple downstream targets via retinoic acid response elements. Biochemical evidence suggests RARα performs two opposing functions, one as a repressor of gene expression in the absence of ligand, the second as a transcriptional activator in the presence of ligand, each controlled by multimeric complexes of transcription corepressors and coactivators. The fusion gene product PML-RARα causes the chimeric receptor to bind more tightly to the nuclear corepressor factor. Therefore, the gene cannot be activated with physiologic doses of retinoic acid. RA induces the differentiation of leukemic cells into mature granulocytes and complete remissions in a majority of patients with APL. Although well tolerated, this therapeutic regimen may be associated with a toxic side effect known as retinoic acid syndrome (RAS), characterized by fever, dyspnea, pulmonary edema and infiltrates. The increased production of inflammatory cytokines (IFN-γ and IL-1β) by myeloid cells and an aberrant interaction between maturating granulocytes and host tissues contribute to RAS pathogenesis. Normal granulocytes do not express CD38, while RA-treated APL/AML cells express high amounts of this molecule (Drach et al., 1994; Mehta and Cheema, 1999). The aberrant expression of CD38 on leukemic cells enhances their propensity to interact with CD31, expressed by lung endothelial cells, resulting in a local production of inflammatory cytokines, apoptosis of endothelial cells and development of RAS (Gao et al., 2007).


Pubmed IDLast YearTitleAuthors
184246642008CD38 gene polymorphism and chronic lymphocytic leukemia: a role in transformation to Richter syndrome?Aydin S et al
72373851981A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis.Binet JL et al
126158942003B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor.Chiorazzi N et al
209569832011Prognostic factors in chronic lymphocytic leukemia-what do we need to know?Cramer P et al
127639262003CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells.Deaglio S et al
95519961998Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member.Deaglio S et al
176997422007CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential.Deaglio S et al
87264001996All-trans retinoic acid (ATRA) and the regulation of adhesion molecules in acute myeloid leukemia.Di Noto R et al
179419522007Chronic lymphocytic leukaemia and small lymphocytic lymphoma: overview of the descriptive epidemiology.Dores GM et al
75110501994Retinoic acid-induced expression of CD38 antigen in myeloid cells is mediated through retinoic acid receptor-alpha.Drach J et al
100885971999The metamorphosis of a molecule: from soluble enzyme to the leukocyte receptor CD38.Ferrero E et al
103699161999The human CD38 gene: polymorphism, CpG island, and linkage to the CD157 (BST-1) gene.Ferrero E et al
169201922007Retinoic acid-induced CD38 antigen promotes leukemia cells attachment and interferon-gamma/interleukin-1beta-dependent apoptosis of endothelial cells: implications in the etiology of retinoic acid syndrome.Gao Y et al
152193862004CD38 polymorphisms in Spanish patients with systemic lupus erythematosus.González-Escribano MF et al
161567812005Second messenger function and the structure-activity relationship of cyclic adenosine diphosphoribose (cADPR).Guse AH et al
182162932008Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines.Hallek M et al
176640182007Cyclic ADP-ribose as a universal calcium signal molecule in the nervous system.Higashida H et al
192402432009CD38 gene polymorphisms contribute to genetic susceptibility to B-cell chronic lymphocytic leukemia: evidence from two case-control studies in Polish Caucasians.Jamroziak K et al
172877292007CD38 is critical for social behaviour by regulating oxytocin secretion.Jin D et al
217908942011Advances in therapies for acute promyelocytic leukemia.Kamimura T et al
210297762010New insights into the pathogenesis of chronic lymphocytic leukemia.Klein U et al
173801982006Structure and enzymatic functions of human CD38.Lee HC et al
211822062010Low CD38 expression in lymphoblastoid cells and haplotypes are both associated with autism in a family-based study.Lerer E et al
161540902005Crystal structure of human CD38 extracellular domain.Liu Q et al
217650222011CD38 and chronic lymphocytic leukemia: a decade later.Malavasi F et al
96377161998Characterization of a CD38-like 78-kilodalton soluble protein released from B cell lines derived from patients with X-linked agammaglobulinemia.Mallone R et al
100484161999Retinoid-mediated signaling pathways in CD38 antigen expression in myeloid leukemia cells.Mehta K et al
204353662010Two genetic variants of CD38 in subjects with autism spectrum disorder and controls.Munesue T et al
107816102000Identification of the enzymatic active site of CD38 by site-directed mutagenesis.Munshi C et al
90745081997Human gene encoding CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase): organization, nucleotide sequence and alternative splicing.Nata K et al
214103732011Multiple myeloma.Palumbo A et al
11390391975Clinical staging of chronic lymphocytic leukemia.Rai KR et al
215281552011All-trans retinoic acid upregulates reduced CD38 transcription in lymphoblastoid cell lines from Autism spectrum disorder.Riebold M et al
212127932011E2A is a transcriptional regulator of CD38 expression in chronic lymphocytic leukemia.Saborit-Villarroya I et al
201415722010CD38/cyclic ADP-ribose system: a new player for oxytocin secretion and regulation of social behaviour.Salmina AB et al
213561862011The prognostic significance of cytogenetics and molecular profiling in multiple myeloma.Sawyer JR et al
173802032006CD38 as a therapeutic target.Stevenson GT et al
220465722011Antibody-based therapies in multiple myeloma.Tai YT et al
86631501996Post-translational modification of CD38 protein into a high molecular weight form alters its catalytic properties.Umar S et al
202207742010CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells.Vaisitti T et al
199561732010From pathogenesis to treatment of chronic lymphocytic leukaemia.Zenz T et al
222899182012The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells.Zucchetto A et al
209669222010Acute promyelocytic leukaemia: novel insights into the mechanisms of Thé H et al
211874432011Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological Weers M et al

Other Information

Locus ID:

NCBI: 952
MIM: 107270
HGNC: 1667
Ensembl: ENSG00000004468


dbSNP: 952
ClinVar: 952
TCGA: ENSG00000004468


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Nicotinate and nicotinamide metabolismKEGGko00760
Calcium signaling pathwayKEGGko04020
Hematopoietic cell lineageKEGGko04640
Nicotinate and nicotinamide metabolismKEGGhsa00760
Calcium signaling pathwayKEGGhsa04020
Hematopoietic cell lineageKEGGhsa04640
Metabolic pathwaysKEGGhsa01100
Salivary secretionKEGGko04970
Salivary secretionKEGGhsa04970
Pancreatic secretionKEGGko04972
Pancreatic secretionKEGGhsa04972
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Oxytocin signaling pathwayKEGGhsa04921
Oxytocin signaling pathwayKEGGko04921
Metabolism of vitamins and cofactorsREACTOMER-HSA-196854
Metabolism of water-soluble vitamins and cofactorsREACTOMER-HSA-196849
Nicotinate metabolismREACTOMER-HSA-196807

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
172877292007CD38 is critical for social behaviour by regulating oxytocin secretion.187
166016732006TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion.122
223365632012Sensitive parenting is associated with plasma oxytocin and polymorphisms in the OXTR and CD38 genes.108
204353662010Two genetic variants of CD38 in subjects with autism spectrum disorder and controls.68
204353662010Two genetic variants of CD38 in subjects with autism spectrum disorder and controls.68
217650222011CD38 and chronic lymphocytic leukemia: a decade later.65
183268212008CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment.60
273072942016CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma.57
156135442005CD38 and CD100 lead a network of surface receptors relaying positive signals for B-CLL growth and survival.55
176841542007CD38 expression labels an activated subset within chronic lymphocytic leukemia clones enriched in proliferating B cells.55


Silvia Deaglio ; Tiziana Vaisitti

CD38 (CD38 molecule)

Atlas Genet Cytogenet Oncol Haematol. 2012-02-01

Online version: