Abstract 1107: β2-integrin-derived signals induce cell survival and proliferation of AML blasts by activating a Syk/STAT signaling axis.
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AbstractConstitutive activation of certain kinase-dependent signal transduction pathways is critical for the pathogenesis of acute myeloid leukemia (AML). Apart from FLT3-ITD the spleen tyrosine kinase (Syk) induces cell survival and proliferation in a high proportion of AML blasts, but the underlying molecular events of Syk signaling have not been investigated so far. Using a phosphoproteomic approach we elucidated the AML-specific phosphorylation state of Syk and found that the kinase is constitutively phosphorylated at all known activation inducing tyrosine residues. Moreover, we have identified the multi-protein complex that is nucleated by constitutively active Syk in AML cells by quantitative proteomic techniques. This complex differs from the B lymphoid Syk interactome regarding several proteins, in particular theβ2-integrin receptor Mac-1 and also the oncogenic transcription factors STAT3 and STAT5. Our functional studies in primary AML cell cultures revealed that tonic signals derived from the integrin-associated Fc-γ chain lead to Syk-dependent activation of STAT3 and STAT5 that in turn induces AML cell proliferation. Moreover, stimulation of Mac-1 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 induce proliferation of AML cells in an AML cell/stroma co-culture model. Taken together, we identified an oncogenic integrin/Syk/STAT signaling axis that might serve as a therapeutic target of AML in the future.Citation Format: Thomas Oellerich, Mark Oellerich, Michael Engelke, Silvia Muench, Sebastian Mohr, He-Hsuan Hsiao, Jing Zhang, Hanibal Bohnenberger, Tobias Berg, Michael Rieger, Juergen Wienands, Gesine Bug, Christian Brandts, Henning Urlaub, Hubert Serve. β2-integrin-derived signals induce cell survival and proliferation of AML blasts by activating a Syk/STAT signaling axis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1107. doi:10.1158/1538-7445.AM2013-1107
