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CD38 modulates CXCR4 signals in chronic lymphocytic leukemia cells: potential therapeutic implications

ABSTRACT: Recent data indicate that CD38, a cell surface enzyme and receptor, is part of the complex network of signals underlying the development, maintenance and progression of chronic lymphocytic leukemia (CLL). Here we show that CD38 signals directly facilitate short- (ERK1/2 phosphorylation) and long-term (chemotaxis) effects induced by CXCL12 exposure. Use of i) a specific enzyme inhibitor, ii) an agonistic anti-CD38 monoclonal antibody (mAb) and iii) microarray studies led to the conclusion that the receptor-like functions of CD38 are responsible for the observed effects. Interactions between CD38 and its non substrate ligand CD31 define a genetic signature characterized by modulation of a significant number of genetic pathways, involved in proliferation and migration. Blocking CD38 with domain-specific mAbs significantly lowers CXCL12 effects, in terms of ERK1/2 phosphorylation and chemotaxis. The molecular explanation behind the blocking activity of these mAbs lies in physical proximity between CD38 and the CXCL12 receptor CXCR4, as demonstrated by i) co-immunoprecipitation, ii) confocal microscopy and iii) direct measurement of CXCL12 binding to its receptor. Lastly, blocking anti-CD38 mAbs were successfully used in vivo to interfere with CLL cell recirculation from blood to the lymphoid organs, an event critically controlled by CXCL12. These results represent a first step towards the validation of anti-CD38 mAbs as potential therapeutics for certain CLL patients. Keywords: gene expression profiling by microarray, CLL, CD31, CD38

ORGANISM(S): Homo sapiens

PROVIDER: GSE14063 | GEO | 2009/12/22

SECONDARY ACCESSION(S): PRJNA112431

REPOSITORIES: GEO

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The enzymatic activities of CD38 enhance CLL growth and trafficking: implications for therapeutic targeting

Project description:The ecto-enzyme CD38 is a marker of unfavorable prognosis for chronic lymphocytic leukemia (CLL) patients and an indicator of activation and proliferation of leukemic cells. Here we show that CD38 is enzymatically active in primary CLL cells and that its forced expression increases disease aggressiveness in a xenograft model. The effect is completely lost when using an enzyme deficient version of CD38 with a single amino-acid mutation. Through the enzymatic conversion of NAD, CD38 increases cytoplasmic Ca2+ concentrations, positively influencing proliferation, chemotaxis, adhesion and matrix digestion. Inhibition of the enzymatic activities of CD38 using the flavonoid kuromanin blocks CLL homing. In a short-term xenograft model using primary cells, kuromanin treatment traps CLL cells in the blood, increasing responses to chemotherapy.

2014-04-01 | GSE56369 | GEO

Transcriptomal changes during differentiation of human iPS cells to PGC-like cells

Project description:Pluripotent stem cell-derived human primordial germ cell (PGC)-like cells (hPGCLCs) may provide important opportunities to study human PGCs. We produced CD38+ hPGCLCs with a high efficiency [~43% of FACS-sorted embryoid body (EB) cells] from primed-pluripotency induced pluripotent stem cells (iPSCs) via 72-hour reprogramming towards ERK-independent naïve pluripotency. RNA-seq confirmed transcriptomal consistency of our hPGCLCs with hPGCLCs previously produced using various other methods. Immunohistochemical studies identified hPGCLCs exclusively at the outermost surface layer of EBs mostly as scattered cells, and live cell imaging revealed actively migrating hPGCLCs forming cellular protrusions. Both CD38+ hPGCLCs and CD38- EB cells significantly expressed PRDM1 and TFAP2C, but PRDM1 mRNA of CD38- cells lacked the 3’-untranslated region with let-7 and other miRNA binding sites known to regulate PRDM1 mRNA stability. Genes expressed specifically in hPGCLCs included early-PGC markers KIT, NANOS3, and SOX17, and cell migration genes, and their promoter sequences were enriched with TFAP2C binding motif. Whereas all hPGCLCs strongly expressed the CXCR4 chemotaxis receptor, its ligand CXCL12/SDF1 was not significantly expressed in the whole EBs. Exposure of hPGCLCs to CXCL12/SDF1 induced cell migration and anti-apoptosis genes; in contrast, genes involved in nuclear division were suppressed. Our study demonstrates a transcriptomal consistency of hPGCLCs produced using varying methods as well as distinct roles and/or regulation of PRDM1 and TFAP2C expression in development of human and mouse PGCs. Relevance of hPGCLCs to early-stage human embryonic PGCs randomly migrating in the midline region of human embryos before initiating directional chemotaxis under CXCR4-CXCL12/SDF1 signaling has also been suggested.

2017-12-06 | GSE102943 | GEO

The enzymatic activities of CD38 enhance CLL growth and trafficking: implications for therapeutic targeting

2014-04-01 | E-GEOD-56369 | biostudies-arrayexpress

Homo sapiens

Project description:CLL: CD38+CD49d+ vs. CD38-CD49d-

| PRJNA111739 | ENA

SLAMF1/CD150 regulates chemotaxis, autophagy and therapy responses in chronic lymphocytic leukemia patients

Project description:This work shows that signaling-lymphocytic-activation-molecule-1 (SLAMF1), a co-stimulatory molecule and a microbial sensor, is expressed by normal CD19+/CD5+ B-lymphocytes. Its expression is lost in a subset of patients with chronic lymphocytic leukemia (CLL) characterized by an aggressive form of the disease, with shorter time to first treatment and overall survival. Silencing of SLAMF1 in the CLL-like Mec-1 cell line (constitutively SLAMF1+) modulated pathways connected to cell migration, cytoskeletal organization and intracellular vesicle formation/recirculation. Loss of SLAMF1 was associated to increased expression of CXCR4, CD38 and CD44, positively affecting chemotactic responses to CXCL12. Ligation of SLAMF1 with an agonistic monoclonal antibody promoted the autophagic flux, by increasing reactive oxygen species (ROS) accumulation and inducing phosphorylation of p38, JNK1/2 and bcl-2. The direct consequence was the assembly of the autophagy macro-complex that included SLAMF1, the scaffold protein Beclin1 and the enzyme Vps34. Consistently, SLAMF1-silenced cells or SLAMF1low primary CLL cells were resistant to autophagy-activating therapeutic agents, such as fludarabine or the BH3 mimetic ABT-737. These results indicate that loss of SLAMF1 expression modulates genetic pathways regulating chemotaxis and autophagy and potentially affecting drug responses, thus providing a likely explanation for the unfavorable clinical outcome experienced by this patient subset. Microarrays were performed comparing genetic signature of CLL-like Mec-1 cell line (constitutively SLAMF1+), transfected with a non-effective (scrambled) shRNA cassette (TR30013) used as control, and a Mec-1 variant generated silencing SLAMF1 gene using pGFP-V-RS construct for SLAMF1 shRNA (TG309422). For each cell line variants, grown in vitro in complete medium, three biological replicates were included in the chip.

2015-05-23 | E-GEOD-69165 | biostudies-arrayexpress

CLL: CD38+CD49d+ vs. CD38-CD49d-

Project description:CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Despite evidence that both molecules are involved in interactions occurring between CLL and normal cells in the context of CLL-involved tissues, a functional link is still missing. Using gene expression profiles comparing CD38+CD49d+ vs. CD38-CD49d- CLL cells, we demonstrated overexpression of the CCL3 and CCL4 chemokines in cells from the former group. These chemokines were also upregulated by CD38 signals in CLL; moreover, CCL3 was expressed by CLL cells from bone marrow biopsies (BMB) of CD38+CD49d+ but not CD38-CD49d- cases. High levels of CCR1 and, to a lesser extent, CCR5, the receptors for CCL3 and CCL4, were found in CLL-derived monocyte-macrophages. Consistently, CCL3 increased monocyte migration, and CD68+ macrophage infiltration was particularly high in BMB from CD38+CD49d+ CLL. Conditioned media from CCL3-stimulated macrophages induced endothelial cells to express VCAM-1, the CD49d ligand, likely through TNFα over-production. These effects were apparent in BMB from CD38+CD49d+CLL, where lymphoid infiltrates were characterized by a prominent meshwork of VCAM-1+ stromal/endothelial cells. Lastly, CD49d engagement by VCAM-1-transfectants increased viability of CD38+CD49d+ CLL cells. Altogether, CD38 and CD49d can be thought of as a part of a consecutive chain of events ultimately leading to improved survival of CLL cells.

2009-03-03 | GSE14560 | GEO

Analysis of CD38+ and CD38- sub-clones derived from the same CLL patient

Project description:CD38 expression is an important prognostic marker in CLL with high levels of CD38 associated with shorter overall survival. In this study, we used gene expression profiling and protein analysis of highly purified cell-sorted CD38+ and CD38- chronic lymphocytic leukemia cells to elucidate a molecular basis for the association between CD38 expression and inferior clinical outcome. Paired CD38+ and CD38- CLL cells derived from the same patient were shown to be monoclonal by VH gene sequencing but despite this, CD38+ CLL cells possessed a distinct gene expression profile when compared with their CD38- sub-clones. Keywords: Sub-clonal analysis of CLL cells derived from the same leukemia sample

2006-11-23 | GSE6321 | GEO

Chronic lymphocytic leukemia cells are activated and proliferate in response to specific Th cells

Project description:Changes in gene expression profile of CLL cells in response to an antigen-specific Th cell clone that is specific for a Ckappa peptide of mouse Abs. Mouse anti human BCR mAbs were used to ligate BCR and deliver antigen to CLL cells. 32-45 x10e6 PBMC were incubated overnight with or without 2 μg/ml of Ms κ+IgG anti-kappa and anti-lambda mAbs. The PBMC were then cultured in presence or absence of 12.5 x10e6 T18 cells. On day 3, CLL cells were purified by negative selection using CD3 and CD14 Dynabeads (Invitrogen). RNA from CLL cells was controlled and quantified on a NanoDrop1000 (Thermo Scientific, Wilmington, DE, USA). 290ng per sample was amplified and labeled with the TotalPrep™-96 RNA Amplification Kit (Illumina, San Diego, CA, USA). Sample quality was further tested by Agilent 2100 bioanalyzer (Agilent, Santa Clara, CA, USA). 1500ng of biotin labeled cRNA was used to hybridize onto Illumina HumanWG-6 v3 Expression BeadChips. After scanning, the results were imported into Illumina GenomeStudio v. 2010.1, Gene Expression module v. 1.6.0 for quality control and data export. Analysis was performed utilizing GeneSpring GX v11 software (Agilent, Santa Clara, CA, USA). In GeneSpring GX, Logbase 2-transformed data were normalized to the 75 percentile with baseline transformation to median of all samples. Flag Information: Lower cutoff for 'Present' call: 0.8, Upper cutoff for 'Absent' call: 0.6 Testing antigen dependent Th cell - CLL cell collaboration, effects on gene expression of CLL cells

2013-08-08 | E-GEOD-48268 | biostudies-arrayexpress

Transcription profiling of CD38+ and CD38- cells derived from the same CLL patient reveals distinct gene expression signatures despite their monoclonal origin.

Project description:CD38 expression is an important prognostic marker in CLL with high levels of CD38 associated with shorter overall survival. In this study, we used gene expression profiling and protein analysis of highly purified cell-sorted CD38+ and CD38- chronic lymphocytic leukemia cells to elucidate a molecular basis for the association between CD38 expression and inferior clinical outcome. Paired CD38+ and CD38- CLL cells derived from the same patient were shown to be monoclonal by VH gene sequencing but despite this, CD38+ CLL cells possessed a distinct gene expression profile when compared with their CD38- sub-clones. Experiment Overall Design: These experiments compared the gene expression profile of CD38+ and CD38- sub-clones derived from 6 individual CLL patients.

2007-11-11 | E-GEOD-6321 | biostudies-arrayexpress

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