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Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1397-1405
The Chimeric E2A-HLF Transcription Factor Abrogates p53-Induced
Apoptosis in Myeloid Leukemia Cells
Rachel A. Altura,
Takeshi Inukai,
Richard A. Ashmun,
Gerard P. Zambetti,
Martine F. Roussel, and
A. Thomas Look
From the Departments of Experimental Oncology, Biochemistry, and
Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN;
and the Department of Pediatrics, University of Tennessee College of
Medicine, Memphis, TN.
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  -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 (M1p53tsval) 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
E2A-HLF into M1p53tsval cells and found that they were
resistant to p53-mediated apoptosis and that E2A-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 E2A-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 M1p53tsval 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 E2A-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.
© 1998 by The American Society of Hematology.
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