The t(3;21) Fusion Product, AML1/Evi-1, Interacts With Smad3 and Blocks Transforming Growth Factor-beta -Mediated Growth Inhibition of Myeloid Cells

The t(3;21)(q26;q22) chromosomal translocation associated withblastic crisis of chronic myelogenous leukemia results in the formationof the AML1/Evi-1 chimeric protein, which is thought to play acausative role in leukemic transformation of hematopoietic cells. Herewe show that AML1/Evi-1 represses growth-inhibitory signaling bytransforming growth factor- (TGF-) in 32Dcl3 myeloid cells. Theactivity of AML1/Evi-1 to repress TGF- signaling depends on the twoseparate regions of the Evi-1 portion, one of which is the first zincfinger domain. AML1/Evi-1 interacts with Smad3, an intracellularmediator of TGF- signaling, through the first zinc finger domain,and represses the Smad3 activity, as Evi-1 does. We also show thatsuppression of endogenous Evi-1 in leukemic cells carrying inv(3)restores TGF- responsiveness. Taken together, AML1/Evi-1 acts as aninhibitor of TGF- signaling by interfering with Smad3 through theEvi-1 portion, and both AML1/Evi-1 and Evi-1 repress TGF--mediatedgrowth suppression in hematopoietic cells. Thus, AML1/Evi-1 maycontribute to leukemogenesis by specifically blocking growth-inhibitorysignaling of TGF- in the t(3;21) leukemia.