THE NOVEL PRIMARY RESPONSE GENE MYD118 AND THE PROTOONCOGENES MYB, MYC, AND BCL-2 MODULATE TRANSFORMING GROWTH FACTOR-BETA-1-INDUCED APOPTOSIS OF MYELOID-LEUKEMIA CELLS

Cell numbers are regulated by a balance among proliferation, growth ar rest, and programmed cell death. A profound example of cell homeostasi s, controlled throughout life, is the complex process of blood cell de velopment, yet little is understood about the intracellular mechanisms that regulate blood cell growth arrest and programmed cell death. In this work, using transforming growth factor beta1 (TGFbeta1)-treated M 1 myeloid leukemia cells and genetically engineered M1 cell variants, the regulation of growth arrest and apoptosis was dissected. Blocking of early expression of MyD118, a novel differentiation primary respons e gene also shown to be a primary response gene induced by TGFbeta1, d elayed TGFbeta1-induced apoptosis, demonstrating that MyD118 is a posi tive modulator of TGFbeta1-mediated cell death. Elevated expression of bcl-2 blocked the TGFbeta1-induced apoptotic pathway but not growth a rrest induced by TGFbeta1. Deregulated expression of either c-myc or c -myb inhibited growth arrest and accelerated apoptosis, demonstrating for the first time that c-myb plays a role in regulating apoptosis. In all cases, the apoptotic response was correlated with the level of My D118 expression. Taken together, these findings demonstrate that the p rimary response gene MyD118 and the c-myc, c-myb, and bcl-2 proto-onco genes interact to modulate growth arrest and apoptosis of myeloid cell s.