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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4344-4352
CBF -SMMHC, Expressed in M4eo Acute Myeloid Leukemia,
Reduces p53 Induction and Slows Apoptosis in Hematopoietic Cells
Exposed to DNA-Damaging Agents
Martin Britos-Bray,
Manuel Ramirez,
Wangsen Cao,
Xinping Wang,
P.
Paul Liu,
Curt I. Civin, and
Alan D. Friedman
From The Johns Hopkins Oncology Center, Division of Pediatric
Oncology, Baltimore, MD; and the National Human Genome Research
Institute, Bethesda, MD.
CBF -SMMHC is expressed in M4Eo acute myeloid leukemia (AML) as a
result of inv(16), but how it contributes to leukemogenesis is
unknown. p53 mutations are rare in de novo AML, but they
are common in many malignancies. Expression of CBF-SMMHC in Ba/F3 cells reduced p53 induction in response to ionizing radiation or
etoposide 3- to 4-fold. However, p53 induction was normal in Ba/F3
cells expressing a CBF-SMMHC variant that does not interfere with
DNA binding by CBF, indicating that a CBF genetic target regulates p53
induction. The p53 gene may be regulated by CBF, because p53 mRNA
levels were reduced by CBF-SMMHC. Reduced p53 induction was not
caused by slowed cell proliferation, a consequence of CBF-SMMHC
expression, because p53 was induced similarly in control cultures and
in cultures propagated in 10-fold less interleukin-3 (IL-3).
CBF-SMMHC did not slow apoptosis resulting from IL-3 withdrawal,
where p53 induction is minimal, but slowed apoptosis in Ba/F3 cells
exposed to 10 Gy of ionizing radiation or 3 to 8 µg/mL etoposide,
providing 2-fold protection at 6 or 18 hours. Inhibition of apoptosis
was temporary, because all the cells exposed to these doses ultimately
died, and clonal survival assays performed using 0.04 µg/mL etoposide
did not show protection by CBF-SMMHC. p21 levels were increased in
cells subjected to DNA damage, regardless of CBF-SMMHC expression
and attenuated p53 induction. Bcl-2, bcl-xL,
bcl-xS, and bax levels were unaffected by CBF-SMMHC. Attenuated p53 induction may contribute to leukemogenesis by
CBF-SMMHC by slowing apoptosis via a p21-independent mechanism.
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