A-myb rescues murine B-cell lymphomas from IgM-receptor-mediated apoptosis through c-myc transcriptional regulation.
A-myb is a member of the myb family of transcription factors, which regulates proliferation, differentiation, and apoptosis of hematopoietic cells. A-Myb expression is normally restricted to the proliferating B-cell centroblasts and transgenic mice overexpressing A-myb displayed enhanced hyperplasia of the lymph nodes. Because A-Myb is highly expressed in several subtypes of human B-cell neoplasias, we sought to determine whether the A-myb gene promoted proliferation and survival of B lymphocytes, using the WEHI 231 and CH33 murine B-cell lymphomas as models. Here, we show that ectopic expression of A-myb rescues WEHI 231 and CH33 cells from growth arrest and apoptosis induced by anti-IgM treatment. Previously, we demonstrated an essential role of the c-myc gene in promoting cell survival of WEHI 231 cells in response to a variety of apoptotic stimuli. Furthermore, we and others have shown that the c-myc gene is potently transactivated by A-Myb in several cell types. Thus, we sought to determine whether c-Myc would mediate the A-Myb antiapoptotic effect in B cells. Here we show that ectopic expression of A-myb leads to maintenance of c-myc expression, and that expression of antisense c-myc RNA ablates A-Myb-mediated survival signals. Thus, these findings strongly implicate the A-myb gene in the regulation of B-cell survival and confirm the c-myc gene as one of the downstream targets of A-myb in these cells. Overall, our observation suggests that A-myb expression may be relevant to the pathology of human B-cell neoplasias.
Department of Biochemistry, Boston University School of Medicine, MA 02118, USA. marsura@bu.edu
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M
Arsura
C S
CS
Hofmann
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Golay
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Introna
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GE
Sonenshein
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D020570:Genes, myb; D016259:Genes, myc; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020598:Proto-Oncogene Proteins c-myb; D011961:Receptors, Fc / Q000235:genetics* / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics; D014158:Transcription, Genetic
C088831:MYBL1 protein, human; C490283:Mybl1 protein, mouse; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D011961:Receptors, Fc; D015534:Trans-Activators; C035311:immunoglobulin M receptor