OVEREXPRESSION OF CORE-BINDING FACTOR-ALPHA (CBF-ALPHA) REVERSES CELLULAR-TRANSFORMATION BY THE CBF-BETA-SMOOTH MUSCLE MYOSIN HEAVY-CHAIN CHIMERIC ONCOPROTEIN

A fusion between the transcription factor core-binding factor beta (CB F beta; also known as PEBP2 beta) and the tail region of smooth muscle myosin heavy chain (SMMHC) is generated by an inversion of chromosome 16 [inv(16) (p13q22)] associated with the M4Eo subtype of acute myelo id leukemia. We have previously shown that this CBF beta-SMMHC chimeri c protein can transform NIH 3T3 cells and that this process requires r egions of the chimeric protein necessary for association with the CBF alpha subunit. In this study, we show that NIH 3T3 cells overexpressin g murine Cbf alpha 2 (also known as Aml1) cannot be transformed by CBF beta-SMMHC and that overexpression of Cbf alpha 2 in cells previously transformed by CBF beta-SMMHC reverts the cells to a less transformed phenotype. Cbf alpha 2 overexpression does not cause any gross morpho logical changes to NIH 3T3 cells but does result in increased CBF acti vity, as indicated by electrophoretic mobility shift assays and transa ctivation of reporter constructs. Cells transformed by CBF beta-SMMHC lack normal CBF-DNA complexes and have decreased levels of transactiva tion. Reversion of CBF beta-SMMHC transformation by Cbf alpha 2 is ass ociated with a restoration of normal CBF-DNA complexes and transactiva tion activity. A Cbf alpha 2 mutant lacking transactivation properties does not transform cells when overexpressed, nor does it protect cell s from CBF beta-SMMHC transformation. These results suggest that CBF b eta-SMMHC interferes with the normal function of CBF and that this int erference is necessary but not sufficient for cellular transformation.