Project name: Homo sapiens

Description: 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, CD38Overall design: CLL cells from 10 patients were immediately collected (“basal” profile) or cultured for 5 days in the presence of L-CD31+ transfectants (“L-CD31+” profile) or mock-transfectants, used as controls (“L-mock” profile). Extracted RNA was co-hybridized to arrays representing 41,000 human unique genes and transcripts to define a genome-wide signature of the events taking place after CD31/CD38 interactions.

Data type: Transcriptome or Gene expression

Sample scope: Multiisolate

Relevance: Medical

Release date: 2009-12-22

Last updated: 2008-12-19