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Acceleration of G₁ Cooperates with Core Binding Factor ß-Smooth Muscle Myosin Heavy Chain to Induce Acute Leukemia in Mice¹

Department of Oncology, Johns Hopkins University, Baltimore, Maryland 21231

The genes encoding the AML1 (RUNX1) or CBFß subunits of core binding factor (CBF) are commonly altered by translocation or mutation in human leukemias. Because CBF oncoproteins slow G₁, we sought to determine whether mutations that accelerate G₁ potentiate their ability to induce transformation. Wild-type or p16^INK4ap19^ARF (-/-) marrow cells transduced with CBFß-smooth muscle myosin heavy chain (SMMHC) were transplanted into wild-type, syngeneic recipients. CBFß-SMMHC significantly increased the development of acute leukemias from marrow lacking the overlapping p16p19 genes, based on analysis of Kaplan-Meier event-time distributions. Wild-type marrow was also transduced with vectors expressing either E7 alone or both E7 and CBFß-SMMHC. Combining oncogenes again increased leukemia formation. Exposing mice transplanted with CBFß-SMMHC-transduced cells to a mutagen, ethylnitrosourea, markedly accelerated leukemogenesis compared to expressing CBFß-SMMHC with loss of p16p19, indicating the need for multiple "hits" for transformation. The INV/p16p19 and INV/E7 leukemias were lymphoid and were clonal and retransplantable. Overall, these findings indicate that CBF mutations cooperate with genetic alterations that accelerate G₁ to induce acute leukemia.

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