Temporal gene expression profile of human precursor B leukemia cells induced by adhesion receptor: identification of pathways regulating B-cell survival.
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.
Astier
Anne Laurence
AL
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Xu
Ronghui
R
Svoboda
Marek
M
Hinds
Esther
E
Munoz
Olivier
O
de Beaumont
Rosalie
R
Crean
Colin Daniel
CD
Gabig
Theodore
T
Freedman
Arnold Stephen
AS
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
D005353:Fibronectins; D019012:Integrin beta1; D011107:Polylysine