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J. Exp. Med.,
Volume 189, Number 8, April 19, 1999 1229-1242
By
From the * Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson
University, Philadelphia, Pennsylvania 19107; the Signal transducer and activator of transcription (STAT)5 is constitutively activated in BCR/
ABL-expressing cells, but the mechanisms and functional consequences of such activation are unknown. We show here that BCR/ABL induces phosphorylation and activation of STAT5
by a mechanism that requires the BCR/ABL Src homology (SH)2 domain and the proline-rich
binding site of the SH3 domain. Upon expression in 32Dcl3 growth factor-dependent myeloid
precursor cells, STAT5 activation-deficient BCR/ABL SH3+SH2 domain mutants functioned as tyrosine kinase and activated Ras, but failed to protect from apoptosis induced by
withdrawal of interleukin 3 and/or serum and did not induce leukemia in severe combined immunodeficiency mice. In complementation assays, expression of a dominant-active STAT5B
mutant (STAT5B-DAM), but not wild-type STAT5B (STAT5B-WT), in 32Dcl3 cells transfected with STAT5 activation-deficient BCR/ABL SH3+SH2 mutants restored protection
from apoptosis, stimulated growth factor-independent cell cycle progression, and rescued the
leukemogenic potential in mice. Moreover, expression of a dominant-negative STAT5B mutant (STAT5B-DNM) in 32Dcl3 cells transfected with wild-type BCR/ABL inhibited apoptosis resistance, growth factor-independent proliferation, and the leukemogenic potential of these
cells. In retrovirally infected mouse bone marrow cells, expression of STAT5B-DNM inhibited BCR/ABL-dependent transformation. Moreover, STAT5B-DAM, but not STAT5B-WT, markedly enhanced the ability of STAT5 activation-defective BCR/ABL SH3+SH2
mutants to induce growth factor-independent colony formation of primary mouse bone marrow
progenitor cells. However, STAT5B-DAM did not rescue the growth factor-independent colony formation of kinase-deficient K1172R BCR/ABL or the triple mutant Y177F+R522L+
Y793F BCR/ABL, both of which also fail to activate STAT5. Together, these data demonstrate
that STAT5 activation by BCR/ABL is dependent on signaling from more than one domain and
document the important role of STAT5-regulated pathways in BCR/ABL leukemogenesis.
Department of Pathology and Laboratory
Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; and the § Department of
Hematopoietic Factors, Institute of Medical Science, University of Tokyo, Tokyo 108, Japan
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