Acceleration of G₁cooperates with core binding factor β-smooth muscle myosin heavy chain to induce acute leukemia in mice

The genes encoding the AML1 (RUNX1) or CBFβ subunits of core binding factor (CBF) are commonly altered by translocation or mutation in human leukemias. Because CBF oncoproteins slow G₁we sought to determine whether mutations that accelerate G₁potentiate their ability to induce transformation. Wild-type or p16^INK4ap19^ARF(-/-) marrow cells transduced with CBFβ-smooth muscle myosin heavy chain (SMMHC) were transplanted into wild-type, syngeneic recipients. CBFβ-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 CBFβ-SMMHC. Combining oncogenes again increased leukemia formation. Exposing mice transplanted with CBFβ-SMMHC-transduced cells to a mutagen, ethylnitrosourea, markedly accelerated leukemogenesis compared to expressing CBFβ-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 G₁to induce acute leukemia.