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.
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19 April 1999
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April 19 1999
Signal Transducer and Activator of Transcription (STAT)5 Activation by BCR/ABL Is Dependent on Intact Src Homology (SH)3 and SH2 Domains of BCR/ABL and Is Required for Leukemogenesis
Malgorzata Nieborowska-Skorska,
Malgorzata Nieborowska-Skorska
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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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Mariusz A. Wasik,
Mariusz A. Wasik
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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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Artur Slupianek,
Artur Slupianek
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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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Paolo Salomoni,
Paolo Salomoni
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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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Toshio Kitamura,
Toshio Kitamura
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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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Bruno Calabretta,
Bruno Calabretta
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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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Tomasz Skorski
Tomasz Skorski
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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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Malgorzata Nieborowska-Skorska
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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
Mariusz A. Wasik
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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
Artur Slupianek
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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
Paolo Salomoni
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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
Toshio Kitamura
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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
Bruno Calabretta
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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
Tomasz Skorski
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡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
Address correspondence to Tomasz Skorski, Department of Microbiology and Immunology, Kimmel Cancer Institute, Jefferson Alumni Hall Rm. 372, 1020 Locust St., Philadelphia, PA 19107. Phone: 215-503-0438; Fax: 215-923-7144; E-mail: [email protected], or to Bruno Calabretta, Kimmel Cancer Institute, BLSB 630, 233 South 10th St., Philadelphia, PA 19107. Phone: 215-503-4523; Fax: 215-923-0249; E-mail: [email protected]
Received:
October 15 1998
Revision Received:
January 13 1999
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1999
J Exp Med (1999) 189 (8): 1229–1242.
Article history
Received:
October 15 1998
Revision Received:
January 13 1999
Citation
Malgorzata Nieborowska-Skorska, Mariusz A. Wasik, Artur Slupianek, Paolo Salomoni, Toshio Kitamura, Bruno Calabretta, Tomasz Skorski; Signal Transducer and Activator of Transcription (STAT)5 Activation by BCR/ABL Is Dependent on Intact Src Homology (SH)3 and SH2 Domains of BCR/ABL and Is Required for Leukemogenesis . J Exp Med 19 April 1999; 189 (8): 1229–1242. doi: https://doi.org/10.1084/jem.189.8.1229
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