title: Temporal gene expression profile of human precursor B leukemia cells induced by adhesion receptor: identification of pathways regulating B-cell survival.
abstract: The physical interactions between B cells and stromal cells from the lymphoid tissue microenvironment are critical to the survival of normal and malignant B cells. They are principally mediated by integrins expressed on B cells and counterreceptors on stromal cells. Specifically, alpha4beta1 integrin engagement rescues B cells from physiological or drug-induced apoptosis. Therefore, in order to understand the mechanisms by which integrins prevent apoptosis in leukemia B cells, we compared the temporal gene expression profiles induced by beta1-integrin ligation with fibronectin (Fn) or adhesion by poly-L-Lysine in serum-starved precursor B leukemia cells. Among the 38 selected differentially expressed genes, 6 genes involved in adhesion (VAV2, EPB41L1, CORO1A), proliferation (FRAP1, CCT4), and intercellular communication (GJB3) were validated by real-time quantitative polymerase chain reaction (RT-Q-PCR). Gene expression modulation could also be validated at the protein level for 5 other genes. We show that integrin stimulation up-regulated FBI-1 expression but inhibited CD79a, Requiem, c-Fos, and caspase 7 induction when the cells underwent apoptosis. We further demonstrate that Fn stimulation also inhibits caspase 3 activation but increases XIAP and survivin expression. Moreover, integrin stimulation also prevents caspase activation induced by doxorubicin. Therefore, we identified genes modulated by adhesion of human precursor B leukemia cells that regulate proliferation and apoptosis, highlighting new pathways that might provide insights into future therapy aiming at targeting apoptosis of leukemia cells.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Anne Laurence
authors.initials: AL
authors.lastname: Astier
authors.forename: Ronghui
authors.initials: R
authors.lastname: Xu
authors.forename: Marek
authors.initials: M
authors.lastname: Svoboda
authors.forename: Esther
authors.initials: E
authors.lastname: Hinds
authors.forename: Olivier
authors.initials: O
authors.lastname: Munoz
authors.forename: Rosalie
authors.initials: R
authors.lastname: de Beaumont
authors.forename: Colin Daniel
authors.initials: CD
authors.lastname: Crean
authors.forename: Theodore
authors.initials: T
authors.lastname: Gabig
authors.forename: Arnold Stephen
authors.initials: AS
authors.lastname: Freedman
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002450:Cell Communication / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D005353:Fibronectins / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011107:Polylysine / Q000494:pharmacology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D005353:Fibronectins; D019012:Integrin beta1; D011107:Polylysine