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β2 integrin–derived signals induce cell survival and proliferation of AML blasts by activating a Syk/STAT signaling axis

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 nucleat...

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Published in:Blood 2013-05, Vol.121 (19), p.3889-3899
Main Authors: Oellerich, Thomas, Oellerich, Mark F., Engelke, Michael, Münch, Silvia, Mohr, Sebastian, Nimz, Marika, Hsiao, He-Hsuan, Corso, Jasmin, Zhang, Jing, Bohnenberger, Hanibal, Berg, Tobias, Rieger, Michael A., Wienands, Jürgen, Bug, Gesine, Brandts, Christian, Urlaub, Henning, Serve, Hubert
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Language:English
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Summary: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. •Integrin signaling promotes proliferative signals in AML cells that are mediated by the kinase Syk and the transcription factors STAT3 and STAT5.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2012-09-457887