The chimeric E2A-HLF transcription factor abrogates p53-induced apoptosis in myeloid leukemia cells

Leukemic lymphoblasts expressing the E2A-HLF oncoprotein possess wild-type p53 genes, but do not undergo apoptosis in response to DNA damage, Experimentally, E2A-HLF prevents apoptosis due to growth factor deprivation or gamma-irradiation in interleukin-3 (IL-3)-dependent murine pro-B cells. To directly test the chimeric protein's ability to abrogate p53-mediated cell death, we used mouse myeloid leukemia cells (M1p53ts(val)) that constitutively express a temperature-sensitive (ts) mutant p53 gene and undergo apoptosis when p53 assumes an active wild-type configuration. This effect is blocked by treatment with IL-6, which allows the cells to survive in culture despite wild-type p53 activation. We introduced EZA-HLF into M1p53ts(val) cells and found that they were resistant to p53-mediated apoptosis and that EZA-HLF effectively substituted for the survival functions of IL-6. The expression of p53-responsive genes such as p21 and Bax was upregulated normally, suggesting that E2A-HLF acts downstream of p53 to block execution of the p53-induced apoptotic program. NFIL3, a growth factor-regulated bZIP protein that binds to the same DNA-consensus site as EZA-HLF, delays apoptosis in IL-3-dependent pro-B cells deprived of growth factor. By contrast, in the present study, enforced expression of NFIL3 failed to protect M1p53ts(val) cells from p53-dependent apoptosis and actively antagonized the ability of IL-6 to rescue cells from that fate, consistent with its role as either a transcriptional repressor or activator, depending on the cell type in which it is expressed. We conclude that the ESA-HLF chimera abrogates p53-induced apoptosis in leukemic cells, possibly through the transcriptional modulation of cell death pathways that are activated by p53 in response to DNA damage. (C) 1998 by The American Society of Hematology.