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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4003-4012
RAPID COMMUNICATION
The t(3;21) Fusion Product, AML1/Evi-1, Interacts With Smad3 and Blocks
Transforming Growth Factor- -Mediated Growth Inhibition of Myeloid
Cells
Mineo Kurokawa,
Kinuko Mitani,
Yoichi Imai,
Seishi Ogawa,
Yoshio Yazaki, and
Hisamaru Hirai
From the Department of Hematology & Oncology, Graduate School of
Medicine, University of Tokyo, Tokyo, Japan.
The t(3;21)(q26;q22) chromosomal translocation associated with
blastic crisis of chronic myelogenous leukemia results in the formation
of the AML1/Evi-1 chimeric protein, which is thought to play a
causative role in leukemic transformation of hematopoietic cells. Here
we show that AML1/Evi-1 represses growth-inhibitory signaling by
transforming growth factor- (TGF-) in 32Dcl3 myeloid cells. The
activity of AML1/Evi-1 to repress TGF- signaling depends on the two
separate regions of the Evi-1 portion, one of which is the first zinc
finger domain. AML1/Evi-1 interacts with Smad3, an intracellular
mediator of TGF- signaling, through the first zinc finger domain,
and represses the Smad3 activity, as Evi-1 does. We also show that
suppression of endogenous Evi-1 in leukemic cells carrying inv(3)
restores TGF- responsiveness. Taken together, AML1/Evi-1 acts as an
inhibitor of TGF- signaling by interfering with Smad3 through the
Evi-1 portion, and both AML1/Evi-1 and Evi-1 repress TGF--mediated
growth suppression in hematopoietic cells. Thus, AML1/Evi-1 may
contribute to leukemogenesis by specifically blocking growth-inhibitory
signaling of TGF- in the t(3;21) leukemia.
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