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 arrest, and programmed cell death. A profound example of cell homeostasis, controlled throughout life, is the complex process of blood cell development, 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 M1 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 response gene also shown to be a primary response gene induced by TGFbeta1, delayed TGFbeta1-induced apoptosis, demonstrating that MyD118 is a positive modulator of TGFbeta1-mediated cell death. Elevated expression of bcl-2 blocked the TGFbeta1-induced apoptotic pathway but not growth arrest 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 MyD118 expression. Taken together, these findings demonstrate that the primary response gene MyD118 and the c-myc, c-myb, and bcl-2 proto-oncogenes interact to modulate growth arrest and apoptosis of myeloid cells.