A-myb rescues murine B-cell lymphomas from IgM-receptor-mediated apoptosisthrough c-myc transcriptional regulation

A-myb is a member of the myb family of transcription factors, which regulat es proliferation, differentiation, and apoptosis of hematopoietic cells, A- Myb expression is normally restricted to the proliferating B-cell centrobla sts 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 p romoted proliferation and survival of B lymphocytes, using the WEHI 231 and CH33 murine B-cell lymphomas as models. Here, we show that ectopic express ion of A-myb rescues WEHI 231 and CH33 cells from growth arrest and apoptos is 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 resp onse to a variety of apoptotic stimuli, Furthermore, we and others have sho wn 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 a ntiapoptotic effect in B cells, Here we show that ectopic expression of A-m yb leads to maintenance of c-myc expression, and that expression of antisen se 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 c ells. Overall, our observation suggests that A-myb expression may be releva nt to the pathology of human B-cell neoplasias. (C) 2000 by The American So ciety of Hematology.