Core Binding Factor (CBF) is required for the development of de®nitive hematopoiesis, and the CBF oncoproteins AML1-ETO, TEL-AML1, and CBFb-SMMHC are commonly expressed in subsets of acute leukemia. CBFb-SMMHC slows the G1 to S cell cycle transition in hematopoietic cells, but the mechanism of this e ect is uncertain. We have sought to determine whether inhibition of CBF-mediated trans-activation is su cient to slow proliferation. We demonstrate that activation of KRAB-AML1-ER, a protein containing the AML1 DNA-binding domain, the KRAB repression domain, and the Estrogen receptor ligand binding domain, also slows G1, if its DNA-binding domain is intact. Also, exogenous AML1 overcame CBFb-SMMHC-induced inhibition of proliferation. Representational di erence analysis (RDA) identi®ed cdk4 RNA expression as an early target of KRAB-AML1 activation. Inhibition of CBF activities by KRAB-AML1-ER or CBFb-SMMHC rapidly reduced endogenous cdk4 mRNA levels, even in cells proliferating at or near control rates as a result of exogenous cdk4 expression. Over-expression of cdk4, especially a variant which cannot bind p16 INK4a , overcame cell cycle inhibition resulting from activation of KRAB-AML1-ER, although cdk4 did not accelerate proliferation when expressed alone. These ®ndings indicate that mutations which alter the expression of G1 regulatory proteins can overcome inhibition of proliferation by CBF oncoproteins.