title: β2 integrin-derived signals induce cell survival and proliferation of AML blasts by activating a Syk/STAT signaling axis.
abstract: Spleen tyrosine kinase (Syk) induces cell survival and proliferation in a high proportion of acute myeloid leukemia (AML) blasts, but the underlying molecular events of Syk signaling have not been investigated. Proteomic techniques have allowed us to identify the multiprotein complex that is nucleated by constitutively active Syk in AML cells. This complex differs from the B-lymphoid Syk interactome with respect to several proteins, especially the integrin receptor Mac-1, the Fc-γ receptor I (FcγRI), and the transcription factors STAT3 and STAT5. We show in several AML cell line models that tonic signals derived from the Fc-γ chain lead to Syk-dependent activation of STAT3 and STAT5, which in turn induces cell survival and proliferation. Moreover, stimulation of Mac-1 or FcγRI intensifies the constitutive Syk-mediated STAT3/5 activation in AML cells, a scenario likely to take place in the bone marrow niche. In accordance with these findings, we observed that β2 integrins, including Mac-1, trigger proliferation of AML cells in an AML cell/stroma coculture model. Taken together, we identified an oncogenic integrin/Syk/STAT3/5 signaling axis that might serve as a therapeutic target of AML in the future.
authors.affiliation: Department of Hematology/Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.forename: Mark F
authors.initials: MF
authors.lastname: Oellerich
authors.forename: Michael
authors.initials: M
authors.lastname: Engelke
authors.forename: Silvia
authors.initials: S
authors.lastname: Münch
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mohr
authors.forename: Marika
authors.initials: M
authors.lastname: Nimz
authors.forename: He-Hsuan
authors.initials: HH
authors.lastname: Hsiao
authors.forename: Jasmin
authors.initials: J
authors.lastname: Corso
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Hanibal
authors.initials: H
authors.lastname: Bohnenberger
authors.forename: Tobias
authors.initials: T
authors.lastname: Berg
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rieger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wienands
authors.forename: Gesine
authors.initials: G
authors.lastname: Bug
authors.forename: Christian
authors.initials: C
authors.lastname: Brandts
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
mesh_terms: D000595:Amino Acid Sequence; D018821:CD18 Antigens / Q000378:metabolism / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured
chemical_list: D018821:CD18 Antigens; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase