Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   
X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

CD38 (CD38 molecule)

Written2012-02Silvia Deaglio, Tiziana Vaisitti
Department of Genetics, Biology, Biochemistry, University of Turin, Turin, Italy

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)T10
HGNC (Hugo) CD38
HGNC Alias nameADP-ribosyl cyclase 1
 NAD(+) nucleosidase
HGNC Previous nameCD38 antigen (p45)
LocusID (NCBI) 952
Atlas_Id 978
Location 4p15.32  [Link to chromosome band 4p15]
Location_base_pair Starts at 15778328 and ends at 15853232 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping CD38.png]
Fusion genes
(updated 2017)		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
RNASE10 (14q11.2)::CD38 (4p15.32)

DNA/RNA

 
  Gene structure of CD38. Colored boxes represent the 8 exons; the total length, the starting and ending base pair of the gene are indicated.
Description 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).
Transcription The mRNA of CD38 (NM_001775.2) contains 1494 bp.

Protein

 
  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.
Description 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 enzyme's 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 enzyme's 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).
Expression 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).
Localisation CD38 is a type II transmembrane protein expressed on plasma and nuclear membranes.
Function 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).
Homology 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).

Mutations

Germinal Not yet reported.

Implicated in

Note
  
Entity Chronic lymphocytic leukemia (CLL)
Disease 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).
Prognosis 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).
Cytogenetics CLL is associated with chromosomal deletions and amplifications: the most frequent is trisomy of chromosome 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).
Oncogenesis 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 Multiple myeloma (MM)
Disease 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.
Prognosis 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).
Cytogenetics 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 (, , ) represent the most common structural abnormalities in MM. Several chromosomal aberrations are acquired during disease progression, involving MYC rearrangements, chromosome 13 (), 17 () 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).
Oncogenesis 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 Acute myeloid leukemia (AML)
Disease 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).
Prognosis 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 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 ( 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.
Oncogenesis 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).
  

To be noted

The human CD38 gene contains a well defined bi-allelic polymorphism that can be identified by the restriction endonuclease PvuII (PvuII site: CAGCTG). The polymorphic site is located at the 5' end of the first intron of the CD38 gene and marks a C→G variation at position 184. The gene frequencies in the healthy population are 0,78 and 0,22 for the C and G allele respectively (CC 61%, GC 33% and GG 6%). The analysis of this polymorphism in a large cohort of CLL patients indicate that the G allele is significantly associated with molecular markers of unfavourable prognosis and represents a significant risk factor for RS transformation (Aydin et al., 2008). The correlation between this polymorphism and genetic susceptibility has been studied also for other diseases, including Systemic Lupus Erythematosus (SLE), where the CC genotype causes susceptibility and the CG genotype confers protection for discoid rash development (Gonzales-Escribano et al., 2004).
Recently, a role for CD38 in mediating oxytocin (OT) release in the brain has been described (Jin et al., 2007). Mice deficient in CD38 lack short term social memory, a defect that has been associated to the autism spectrum disorders (ASD) in humans. Several polymorphism across CD38 gene (rs6449197, rs3796863 and rs1800561) are associated with ASD (Lerer et al., 2010; Munesue et al., 2010) and a correlation between CD38 expression and measure of social function in ASD observed (Riebold et al., 2011). Indeed, a reduced expression of CD38 in lymphoblast from ASD patients compared to parental lymphoblastoid cell lines has been reported. Lower CD38 expression and consequently lower level of activation of its enzymatic functions in ASD can be linked to a dysfunction in OT transmission in this disorder (Higashida et al., 2007; Salmina et al., 2010; Higashida et al., 2010).

Bibliography

CD38 gene polymorphism and chronic lymphocytic leukemia: a role in transformation to Richter syndrome?
Aydin S, Rossi D, Bergui L, D'Arena G, Ferrero E, Bonello L, Omede P, Novero D, Morabito F, Carbone A, Gaidano G, Malavasi F, Deaglio S.
Blood. 2008 Jun 15;111(12):5646-53. Epub 2008 Apr 18.
PMID 18424664
 
A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis.
Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F.
Cancer. 1981 Jul 1;48(1):198-206.
PMID 7237385
 
B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor.
Chiorazzi N, Ferrarini M.
Annu Rev Immunol. 2003;21:841-94. Epub 2001 Dec 19. (REVIEW)
PMID 12615894
 
Prognostic factors in chronic lymphocytic leukemia-what do we need to know?
Cramer P, Hallek M.
Nat Rev Clin Oncol. 2011 Jan;8(1):38-47. Epub 2010 Oct 19. (REVIEW)
PMID 20956983
 
CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells.
Deaglio S, Capobianco A, Bergui L, Durig J, Morabito F, Duhrsen U, Malavasi F.
Blood. 2003 Sep 15;102(6):2146-55. Epub 2003 May 22.
PMID 12763926
 
Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member.
Deaglio S, Morra M, Mallone R, Ausiello CM, Prager E, Garbarino G, Dianzani U, Stockinger H, Malavasi F.
J Immunol. 1998 Jan 1;160(1):395-402.
PMID 9551996
 
CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential.
Deaglio S, Vaisitti T, Aydin S, Bergui L, D'Arena G, Bonello L, Omede P, Scatolini M, Jaksic O, Chiorino G, Efremov D, Malavasi F.
Blood. 2007 Dec 1;110(12):4012-21. Epub 2007 Aug 15.
PMID 17699742
 
All-trans retinoic acid (ATRA) and the regulation of adhesion molecules in acute myeloid leukemia.
Di Noto R, Lo Pardo C, Schiavone EM, Ferrara F, Manzo C, Vacca C, Del Vecchio L.
Leuk Lymphoma. 1996 Apr;21(3-4):201-9. (REVIEW)
PMID 8726400
 
Chronic lymphocytic leukaemia and small lymphocytic lymphoma: overview of the descriptive epidemiology.
Dores GM, Anderson WF, Curtis RE, Landgren O, Ostroumova E, Bluhm EC, Rabkin CS, Devesa SS, Linet MS.
Br J Haematol. 2007 Dec;139(5):809-19. Epub 2007 Oct 17.
PMID 17941952
 
Retinoic acid-induced expression of CD38 antigen in myeloid cells is mediated through retinoic acid receptor-alpha.
Drach J, McQueen T, Engel H, Andreeff M, Robertson KA, Collins SJ, Malavasi F, Mehta K.
Cancer Res. 1994 Apr 1;54(7):1746-52.
PMID 7511050
 
The metamorphosis of a molecule: from soluble enzyme to the leukocyte receptor CD38.
Ferrero E, Malavasi F.
J Leukoc Biol. 1999 Feb;65(2):151-61. (REVIEW)
PMID 10088597
 
The human CD38 gene: polymorphism, CpG island, and linkage to the CD157 (BST-1) gene.
Ferrero E, Saccucci F, Malavasi F.
Immunogenetics. 1999 Jul;49(7-8):597-604.
PMID 10369916
 
Retinoic 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, Camacho LH, Mehta K.
Leuk Res. 2007 Apr;31(4):455-63. Epub 2006 Aug 22.
PMID 16920192
 
CD38 polymorphisms in Spanish patients with systemic lupus erythematosus.
Gonzalez-Escribano MF, Aguilar F, Torres B, Sanchez-Roman J, Nunez-Roldan A.
Hum Immunol. 2004 Jun;65(6):660-4.
PMID 15219386
 
Second messenger function and the structure-activity relationship of cyclic adenosine diphosphoribose (cADPR).
Guse AH.
FEBS J. 2005 Sep;272(18):4590-7. (REVIEW)
PMID 16156781
 
Guidelines 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, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ; International Workshop on Chronic Lymphocytic Leukemia.
Blood. 2008 Jun 15;111(12):5446-56. Epub 2008 Jan 23.
PMID 18216293
 
Cyclic ADP-ribose as a universal calcium signal molecule in the nervous system.
Higashida H, Salmina AB, Olovyannikova RY, Hashii M, Yokoyama S, Koizumi K, Jin D, Liu HX, Lopatina O, Amina S, Islam MS, Huang JJ, Noda M.
Neurochem Int. 2007 Jul-Sep;51(2-4):192-9. Epub 2007 Jun 28. (REVIEW)
PMID 17664018
 
CD38 gene polymorphisms contribute to genetic susceptibility to B-cell chronic lymphocytic leukemia: evidence from two case-control studies in Polish Caucasians.
Jamroziak K, Szemraj Z, Grzybowska-Izydorczyk O, Szemraj J, Bieniasz M, Cebula B, Giannopoulos K, Balcerczak E, Jesionek-Kupnicka D, Kowal M, Kostyra A, Calbecka M, Wawrzyniak E, Mirowski M, Kordek R, Robak T.
Cancer Epidemiol Biomarkers Prev. 2009 Mar;18(3):945-53. Epub 2009 Feb 24.
PMID 19240243
 
CD38 is critical for social behaviour by regulating oxytocin secretion.
Jin D, Liu HX, Hirai H, Torashima T, Nagai T, Lopatina O, Shnayder NA, Yamada K, Noda M, Seike T, Fujita K, Takasawa S, Yokoyama S, Koizumi K, Shiraishi Y, Tanaka S, Hashii M, Yoshihara T, Higashida K, Islam MS, Yamada N, Hayashi K, Noguchi N, Kato I, Okamoto H, Matsushima A, Salmina A, Munesue T, Shimizu N, Mochida S, Asano M, Higashida H.
Nature. 2007 Mar 1;446(7131):41-5. Epub 2007 Feb 7.
PMID 17287729
 
Advances in therapies for acute promyelocytic leukemia.
Kamimura T, Miyamoto T, Harada M, Akashi K.
Cancer Sci. 2011 Nov;102(11):1929-37. doi: 10.1111/j.1349-7006.2011.02045.x. Epub 2011 Aug 24. (REVIEW)
PMID 21790894
 
New insights into the pathogenesis of chronic lymphocytic leukemia.
Klein U, Dalla-Favera R.
Semin Cancer Biol. 2010 Dec;20(6):377-83. Epub 2010 Oct 26. (REVIEW)
PMID 21029776
 
Structure and enzymatic functions of human CD38.
Lee HC.
Mol Med. 2006 Nov-Dec;12(11-12):317-23.
PMID 17380198
 
Low CD38 expression in lymphoblastoid cells and haplotypes are both associated with autism in a family-based study.
Lerer E, Levi S, Israel S, Yaari M, Nemanov L, Mankuta D, Nurit Y, Ebstein RP.
Autism Res. 2010 Dec;3(6):293-302. doi: 10.1002/aur.156.
PMID 21182206
 
Crystal structure of human CD38 extracellular domain.
Liu Q, Kriksunov IA, Graeff R, Munshi C, Lee HC, Hao Q.
Structure. 2005 Sep;13(9):1331-9.
PMID 16154090
 
CD38 and chronic lymphocytic leukemia: a decade later.
Malavasi F, Deaglio S, Damle R, Cutrona G, Ferrarini M, Chiorazzi N.
Blood. 2011 Sep 29;118(13):3470-8. Epub 2011 Jul 15. (REVIEW)
PMID 21765022
 
Characterization of a CD38-like 78-kilodalton soluble protein released from B cell lines derived from patients with X-linked agammaglobulinemia.
Mallone R, Ferrua S, Morra M, Zocchi E, Mehta K, Notarangelo LD, Malavasi F.
J Clin Invest. 1998 Jun 15;101(12):2821-30.
PMID 9637716
 
Retinoid-mediated signaling pathways in CD38 antigen expression in myeloid leukemia cells.
Mehta K, Cheema S.
Leuk Lymphoma. 1999 Feb;32(5-6):441-9. (REVIEW)
PMID 10048416
 
Two genetic variants of CD38 in subjects with autism spectrum disorder and controls.
Munesue T, Yokoyama S, Nakamura K, Anitha A, Yamada K, Hayashi K, Asaka T, Liu HX, Jin D, Koizumi K, Islam MS, Huang JJ, Ma WJ, Kim UH, Kim SJ, Park K, Kim D, Kikuchi M, Ono Y, Nakatani H, Suda S, Miyachi T, Hirai H, Salmina A, Pichugina YA, Soumarokov AA, Takei N, Mori N, Tsujii M, Sugiyama T, Yagi K, Yamagishi M, Sasaki T, Yamasue H, Kato N, Hashimoto R, Taniike M, Hayashi Y, Hamada J, Suzuki S, Ooi A, Noda M, Kamiyama Y, Kido MA, Lopatina O, Hashii M, Amina S, Malavasi F, Huang EJ, Zhang J, Shimizu N, Yoshikawa T, Matsushima A, Minabe Y, Higashida H.
Neurosci Res. 2010 Jun;67(2):181-91. Epub 2010 May 1.
PMID 20435366
 
Identification of the enzymatic active site of CD38 by site-directed mutagenesis.
Munshi C, Aarhus R, Graeff R, Walseth TF, Levitt D, Lee HC.
J Biol Chem. 2000 Jul 14;275(28):21566-71.
PMID 10781610
 
Human gene encoding CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase): organization, nucleotide sequence and alternative splicing.
Nata K, Takamura T, Karasawa T, Kumagai T, Hashioka W, Tohgo A, Yonekura H, Takasawa S, Nakamura S, Okamoto H.
Gene. 1997 Feb 28;186(2):285-92.
PMID 9074508
 
Multiple myeloma.
Palumbo A, Anderson K.
N Engl J Med. 2011 Mar 17;364(11):1046-60. (REVIEW)
PMID 21410373
 
Clinical staging of chronic lymphocytic leukemia.
Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS.
Blood. 1975 Aug;46(2):219-34.
PMID 1139039
 
All-trans retinoic acid upregulates reduced CD38 transcription in lymphoblastoid cell lines from Autism spectrum disorder.
Riebold M, Mankuta D, Lerer E, Israel S, Zhong S, Nemanov L, Monakhov MV, Levi S, Yirmiya N, Yaari M, Malavasi F, Ebstein RP.
Mol Med. 2011;17(7-8):799-806. doi: 10.2119/molmed.2011.00080. Epub 2011 Apr 25.
PMID 21528155
 
E2A is a transcriptional regulator of CD38 expression in chronic lymphocytic leukemia.
Saborit-Villarroya I, Vaisitti T, Rossi D, D'Arena G, Gaidano G, Malavasi F, Deaglio S.
Leukemia. 2011 Mar;25(3):479-88. Epub 2011 Jan 7.
PMID 21212793
 
CD38/cyclic ADP-ribose system: a new player for oxytocin secretion and regulation of social behaviour.
Salmina AB, Lopatina O, Ekimova MV, Mikhutkina SV, Higashida H.
J Neuroendocrinol. 2010 May;22(5):380-92. Epub 2010 Feb 5. (REVIEW)
PMID 20141572
 
The prognostic significance of cytogenetics and molecular profiling in multiple myeloma.
Sawyer JR.
Cancer Genet. 2011 Jan;204(1):3-12. (REVIEW)
PMID 21356186
 
CD38 as a therapeutic target.
Stevenson GT.
Mol Med. 2006 Nov-Dec;12(11-12):345-6.
PMID 17380203
 
Antibody-based therapies in multiple myeloma.
Tai YT, Anderson KC.
Bone Marrow Res. 2011;2011:924058. Epub 2011 Mar 2.
PMID 22046572
 
Post-translational modification of CD38 protein into a high molecular weight form alters its catalytic properties.
Umar S, Malavasi F, Mehta K.
J Biol Chem. 1996 Jul 5;271(27):15922-7.
PMID 8663150
 
CD38 increases CXCL12-mediated signals and homing of chronic lymphocytic leukemia cells.
Vaisitti T, Aydin S, Rossi D, Cottino F, Bergui L, D'Arena G, Bonello L, Horenstein AL, Brennan P, Pepper C, Gaidano G, Malavasi F, Deaglio S.
Leukemia. 2010 May;24(5):958-69. Epub 2010 Mar 11.
PMID 20220774
 
From pathogenesis to treatment of chronic lymphocytic leukaemia.
Zenz T, Mertens D, Kuppers R, Dohner H, Stilgenbauer S.
Nat Rev Cancer. 2010 Jan;10(1):37-50. Epub 2009 Dec 3. (REVIEW)
PMID 19956173
 
The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells.
Zucchetto A, Vaisitti T, Benedetti D, Tissino E, Bertagnolo V, Rossi D, Bomben R, Dal Bo M, Del Principe MI, Gorgone A, Pozzato G, Gaidano G, Del Poeta G, Malavasi F, Deaglio S, Gattei V.
Leukemia. 2012 Jan 6. doi: 10.1038/leu.2011.369. [Epub ahead of print]
PMID 22289918
 
Acute promyelocytic leukaemia: novel insights into the mechanisms of cure.
de The H, Chen Z.
Nat Rev Cancer. 2010 Nov;10(11):775-83. Epub 2010 Oct 22. (REVIEW)
PMID 20966922
 
Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors.
de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DC, Oomen LA, Peipp M, Valerius T, Slootstra JW, Mutis T, Bleeker WK, Anderson KC, Lokhorst HM, van de Winkel JG, Parren PW.
J Immunol. 2011 Feb 1;186(3):1840-8. Epub 2010 Dec 27.
PMID 21187443
 

Citation

This paper should be referenced as such :
Deaglio, S ; Vaisitti, T
CD38 (CD38 molecule)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(7):446-452.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  i(4p) in myeloid malignancies

External links

 

Nomenclature
HGNC (Hugo)CD38   1667
Cards
AtlasCD38ID978ch4p15
Entrez_Gene (NCBI)CD38    CD38 molecule
AliasesADPRC; ADPRC1
GeneCards (Weizmann)CD38
Ensembl hg19 (Hinxton)ENSG00000004468 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000004468 [Gene_View]  ENSG00000004468 [Sequence]  chr4:15778328-15853232 [Contig_View]  CD38 [Vega]
ICGC DataPortalENSG00000004468
TCGA cBioPortalCD38
AceView (NCBI)CD38
Genatlas (Paris)CD38
SOURCE (Princeton)CD38
Genetics Home Reference (NIH)CD38
Genomic and cartography
GoldenPath hg38 (UCSC)CD38  -     chr4:15778328-15853232 +  4p15.32   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CD38  -     4p15.32   [Description]    (hg19-Feb_2009)
GoldenPathCD38 - 4p15.32 [CytoView hg19]  CD38 - 4p15.32 [CytoView hg38]
ImmunoBaseENSG00000004468
Genome Data Viewer NCBICD38 [Mapview hg19]  
OMIM107270   
Gene and transcription
Genbank (Entrez)AA417096 AK297592 AK303169 AK313268 BC007964
RefSeq transcript (Entrez)NM_001775
Consensus coding sequences : CCDS (NCBI)CD38
Gene ExpressionCD38 [ NCBI-GEO ]   CD38 [ EBI - ARRAY_EXPRESS ]   CD38 [ SEEK ]   CD38 [ MEM ]
Gene Expression Viewer (FireBrowse)CD38 [ Firebrowse - Broad ]
GenevisibleExpression of CD38 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)952
GTEX Portal (Tissue expression)CD38
Human Protein AtlasENSG00000004468-CD38 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP28907   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP28907  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP28907
Catalytic activity : Enzyme3.2.2.6 [ Enzyme-Expasy ]   3.2.2.63.2.2.6 [ IntEnz-EBI ]   3.2.2.6 [ BRENDA ]   3.2.2.6 [ KEGG ]   [ MEROPS ]
PhosPhoSitePlusP28907
Domains : Interpro (EBI)ADP-ribosyl_cyclase    CD38   
Domain families : Pfam (Sanger)Rib_hydrolayse (PF02267)   
Domain families : Pfam (NCBI)pfam02267   
Conserved Domain (NCBI)CD38
PDB (RSDB)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    4TMF    4XJS    4XJT    5F1K    5F1O    5F21    6EDR    6VUA   
PDB Europe1YH3    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    4TMF    4XJS    4XJT    5F1K    5F1O    5F21    6EDR    6VUA   
PDB (PDBSum)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    4TMF    4XJS    4XJT    5F1K    5F1O    5F21    6EDR    6VUA   
PDB (IMB)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    4TMF    4XJS    4XJT    5F1K    5F1O    5F21    6EDR    6VUA   
Structural Biology KnowledgeBase1YH3    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    4TMF    4XJS    4XJT    5F1K    5F1O    5F21    6EDR    6VUA   
SCOP (Structural Classification of Proteins)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    4TMF    4XJS    4XJT    5F1K    5F1O    5F21    6EDR    6VUA   
CATH (Classification of proteins structures)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    4TMF    4XJS    4XJT    5F1K    5F1O    5F21    6EDR    6VUA   
SuperfamilyP28907
AlphaFold pdb e-kbP28907   
Human Protein Atlas [tissue]ENSG00000004468-CD38 [tissue]
HPRD00116
Protein Interaction databases
DIP (DOE-UCLA)P28907
IntAct (EBI)P28907
BioGRIDCD38
STRING (EMBL)CD38
ZODIACCD38
Ontologies - Pathways
QuickGOP28907
Ontology : AmiGOresponse to hypoxia  NAD+ nucleosidase activity  nucleus  plasma membrane  plasma membrane  plasma membrane  signal transduction  positive regulation of cytosolic calcium ion concentration  female pregnancy  cell surface  negative regulation of neuron projection development  artery smooth muscle contraction  membrane  integral component of membrane  basolateral plasma membrane  transferase activity  phosphorus-oxygen lyase activity  NAD metabolic process  positive regulation of cell growth  secretory granule membrane  positive regulation of B cell proliferation  positive regulation of B cell proliferation  positive regulation of insulin secretion  response to estradiol  response to retinoic acid  response to progesterone  response to hydroperoxide  response to drug  identical protein binding  negative regulation of apoptotic process  negative regulation of bone resorption  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of vasoconstriction  NAD(P)+ nucleosidase activity  B cell receptor signaling pathway  long-term synaptic depression  NAD+ nucleotidase, cyclic ADP-ribose generating  extracellular exosome  response to interleukin-1  apoptotic signaling pathway  
Ontology : EGO-EBIresponse to hypoxia  NAD+ nucleosidase activity  nucleus  plasma membrane  plasma membrane  plasma membrane  signal transduction  positive regulation of cytosolic calcium ion concentration  female pregnancy  cell surface  negative regulation of neuron projection development  artery smooth muscle contraction  membrane  integral component of membrane  basolateral plasma membrane  transferase activity  phosphorus-oxygen lyase activity  NAD metabolic process  positive regulation of cell growth  secretory granule membrane  positive regulation of B cell proliferation  positive regulation of B cell proliferation  positive regulation of insulin secretion  response to estradiol  response to retinoic acid  response to progesterone  response to hydroperoxide  response to drug  identical protein binding  negative regulation of apoptotic process  negative regulation of bone resorption  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of vasoconstriction  NAD(P)+ nucleosidase activity  B cell receptor signaling pathway  long-term synaptic depression  NAD+ nucleotidase, cyclic ADP-ribose generating  extracellular exosome  response to interleukin-1  apoptotic signaling pathway  
Pathways : KEGGNicotinate and nicotinamide metabolism    Calcium signaling pathway    Hematopoietic cell lineage    Salivary secretion    Pancreatic secretion    Epstein-Barr virus infection   
REACTOMEP28907 [protein]
REACTOME PathwaysR-HSA-196807 [pathway]   
NDEx NetworkCD38
Atlas of Cancer Signalling NetworkCD38
Wikipedia pathwaysCD38
Orthology - Evolution
OrthoDB952
GeneTree (enSembl)ENSG00000004468
Phylogenetic Trees/Animal Genes : TreeFamCD38
Homologs : HomoloGeneCD38
Homology/Alignments : Family Browser (UCSC)CD38
Gene fusions - Rearrangements
Fusion : MitelmanRNASE10::CD38 [14q11.2/4p15.32]  
Fusion : FusionGDB3.2.2.5   
Fusion : QuiverCD38
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCD38 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CD38
dbVarCD38
ClinVarCD38
MonarchCD38
1000_GenomesCD38 
Exome Variant ServerCD38
GNOMAD BrowserENSG00000004468
Varsome BrowserCD38
ACMGCD38 variants
VarityP28907
Genomic Variants (DGV)CD38 [DGVbeta]
DECIPHERCD38 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCD38 
Mutations
ICGC Data PortalCD38 
TCGA Data PortalCD38 
Broad Tumor PortalCD38
OASIS PortalCD38 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCD38  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DCD38
Mutations and Diseases : HGMDCD38
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
BioMutaCD38
DgiDB (Drug Gene Interaction Database)CD38
DoCM (Curated mutations)CD38
CIViC (Clinical Interpretations of Variants in Cancer)CD38
NCG (London)CD38
Cancer3DCD38
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM107270   
Orphanet
DisGeNETCD38
MedgenCD38
Genetic Testing Registry CD38
NextProtP28907 [Medical]
GENETestsCD38
Target ValidationCD38
Huge Navigator CD38 [HugePedia]
ClinGenCD38
Clinical trials, drugs, therapy
MyCancerGenomeCD38
Protein Interactions : CTDCD38
Pharm GKB GenePA26214
PharosP28907
Clinical trialCD38
Miscellaneous
canSAR (ICR)CD38
HarmonizomeCD38
DataMed IndexCD38
Probes
Litterature
PubMed273 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXCD38
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Oct 8 21:14:26 CEST 2021
Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.