c-Myc overcomes cell cycle inhibition by CBFbeta-SMMHC, a myeloid leukemia oncoprotein.

Thirty percent of acute myeloid leukemia cases express a Core Binding Factor (CBF) oncoprotein or harbor point mutations in one or both AML1 (RUNX1) genes. Each of these alterations reduces endogenous CBF activities. CBFbeta-SMMHC is expressed from the inv(16) chromosome in 8% of AML cases and inhibits endogenous CBF DNA-binding.

TEL-AML1, expressed from t(12;21) in human acute lymphocytic leukemia, induces acute leukemia in mice.

TEL-AML1 is expressed from the t(12;21) chromosomal translocation inB-precursor acute lymphocytic leukemia (ALL). Creation of the TEL-AML1fusion disrupts one copy of the TEL and AML1 genes, and loss of TEL or AML1 is also associated with cases of acute leukemia without TEL-AML1. To determine whether TEL-AML1 can contribute to leukemogenesis, we transduced marrow from C57BL/6 mice with a retroviral vector expressing TEL-AML1 or with a control vector.

AML1 stimulates G1 to S progression via its transactivation domain.

Inhibition of AML1-mediated transactivation potently slows G1 to S cell cycle progression. In Ba/F3 cells, activation of exogenous AML1 (RUNX1)-ER with 4-hydroxytamoxifen prevents inhibition of G1 progression mediated by CBFbeta-SMMHC, a CBF oncoprotein. We expressed three AML1-ER variants with CBFbeta-SMMHC in Ba/F3 cells.