CBF-BETA-SMMHC, EXPRESSED IN M4EO ACUTE MYELOID-LEUKEMIA, REDUCES P53INDUCTION AND SLOWS APOPTOSIS IN HEMATOPOIETIC-CELLS EXPOSED TO DNA-DAMAGING AGENTS

CBF beta-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 m alignancies. Expression of CBF beta-SMMHC in Ba/F3 cells reduced p53 i nduction in response to ionizing radiation or etoposide 3- to 4-fold. However, p53 induction was normal in Ba/F3 cells expressing a CBF beta -SMMHC variant that does not interfere with DNA binding by CBF, indica ting that a CBF genetic target regulates p53 induction. The p53 gene m ay be regulated by CBF, because p53 mRNA levels were reduced by CBF be ta-SMMHC. Reduced p53 induction was not caused by slowed cell prolifer ation, a consequence of CBF beta-SMMHC expression, because p53 was ind uced similarly in control cultures and in cultures propagated in 10-fo ld less interleukin-3 (IL-3), CBF beta-SMMHC did not slow apoptosis re sulting from IL-3 withdrawal, where p53 induction is minimal, but slow ed apoptosis in Ba/F3 cells exposed to 10 Gy of ionizing radiation or 3 to 8 mu g/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 mu g/mL etoposide did not show protection by CBF beta-SMMHC . p21 levels were increased in cells subjected to DNA damage, regardle ss of CBF beta-SMMHC expression and attenuated p53 induction. Bcl-2, b cl-x(L), bcl-x(S), and bax levels were unaffected by CBF beta-SMMHC. A ttenuated p53 induction may contribute to leukemogenesis by CBF beta-S MMHC by slowing apoptosis via a p21-independent mechanism. (C) 1998 by The American Society of Hematology.