Multimerization via Its Myosin Domain Facilitates Nuclear Localization and Inhibition of Core Binding Factor (CBF) Activities by the CBF -Smooth Muscle Myosin Heavy Chain Myeloid Leukemia Oncoprotein

The core binding factor (CBF) transcription factors contain one of three CBF␣ subunits, CBF␣1/AML3/RUNX2, CBF␣2/ AML1/RUNX1, or CBF␣3/AML2/RUNX3, and a common CBF␤ subunit (3, 14, 21, 35, 50). The CBF␣ subunits contact the consensus DNA binding site, 5Ј-(Pu)ACCPuCA-3Ј, via their 127-amino-acid Runt homology domains (3, 30). CBF␤ does not bind DNA but increases the DNA affinity of the CBF␣ subunits via allosteric interaction with the Runt domain (36, 47, 50). Amino acids 1 to 137 of the 182-residue CBF␤ are sufficient for increasing the DNA affinity of CBF␣ subunits (16, 19). CBF␤ is widely expressed, whereas AML1 is largely restricted to hematopoietic cells (43, 50). Mice lacking AML1 or CBF␤ do not develop definitive hematopoiesis (33, 37, 42, 51). A role for AML1 during maturation of pluripotent stem cells along the lymphoid and myeloid lineages has been inferred from its ability to transactivate promoters of lineage-restricted genes (34, 41, 46, 58). AML1 possesses only weak intrinsic transactivating potential but cooperates with additional transcription factors to activate genes in hematopoietic cells (7, 40, 46). AML1 is found in the cell nucleus, whereas the large majority of CBF␤ is cytoplasmic, reflecting its expression in excess of CBF␣ and its affinity for the actin cytoskeleton (26, 48). Chromosomal and mutational abnormalities affecting the genes encoding AML1 and CBF␤ are common in acute leu-kemia cases (14). CBF␤-SMMHC, encoded by inv(16) (p13; q22) or t(16;16) (p13;q22) in 8% of acute myeloid leukemias, inhibits CBF activities via its interactions with AML1 (9, 10, 22, 23). In contrast, AML1-ETO, another CBF oncoprotein, directly represses AML1 target genes (31). The phenotypes of AML1-ETO and CBF␤-SMMHC knock-in mice are similar to those lacking AML1 or CBF␤, indicating that these oncoproteins interfere with CBF activities in vivo (11, 38, 57). A direct role for CBF␤-SMMHC in the formation of human acute myeloid leukemias can be inferred from the formation of acute myeloid leukemias in chimeric mice exposed to ethylnitrosourea (12). In addition to stimulating differentiation, CBF is require for the G 1 to S transition in 32D cl3 myeloid and Ba/F3 lymphoid cells (9, 25). Deletion of 11 N-terminal CBF␤ residues required for interaction with AML1 prevents CBF␤-SMMHC from slowing Ba/F3 proliferation, and exogenous AML1 accelerates G 1 progression via transactivation (4, 10, 25, 45). Exog-enous AML1, cdk4, cyclin D2, and c-Myc prevent CBF␤-SMMHC from slowing Ba/F3 proliferation (5, 25). During leukemogenesis, genetic alterations which accelerate G 1 may potentiate …