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, Mariusz A. Wasik, Artur Slupianek, Paolo Salomoni, Toshio Kitamura, Bruno Calabretta, Tomasz Skorski

Research output: Contribution to journalArticlepeer-review

250 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1229-1242
Number of pages14
JournalJournal of Experimental Medicine
Volume189
Issue number8
DOIs
StatePublished - Apr 19 1999

Keywords

  • Animals
  • Apoptosis
  • Bone Marrow Cells/metabolism
  • Cell Cycle/genetics
  • DNA Replication/genetics
  • DNA-Binding Proteins/genetics
  • Genes, abl/genetics
  • Genes, ras/genetics
  • Leukemia/genetics
  • Mice
  • Mice, SCID
  • Milk Proteins
  • Mutation
  • Phosphoproteins/analysis
  • Phosphorylation
  • STAT5 Transcription Factor
  • Signal Transduction/genetics
  • Stem Cells/metabolism
  • Trans-Activators/genetics
  • Transcriptional Activation/genetics
  • src Homology Domains/genetics

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