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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Sequence
-
CD18 Antigens / metabolism
-
CD18 Antigens / physiology*
-
Cell Proliferation*
-
Cell Survival / genetics
-
Cell Survival / physiology
-
Humans
-
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
-
Intracellular Signaling Peptides and Proteins / metabolism*
-
Leukemia, Myeloid, Acute / genetics
-
Leukemia, Myeloid, Acute / metabolism
-
Leukemia, Myeloid, Acute / pathology*
-
Models, Biological
-
Molecular Sequence Data
-
Protein Kinase Inhibitors / metabolism
-
Protein Kinase Inhibitors / pharmacology
-
Protein-Tyrosine Kinases / antagonists & inhibitors
-
Protein-Tyrosine Kinases / metabolism*
-
STAT Transcription Factors / genetics
-
STAT Transcription Factors / metabolism
-
STAT3 Transcription Factor / genetics
-
STAT3 Transcription Factor / metabolism*
-
STAT5 Transcription Factor / genetics
-
STAT5 Transcription Factor / metabolism*
-
Signal Transduction / genetics
-
Signal Transduction / physiology
-
Syk Kinase
-
Tumor Cells, Cultured
Substances
-
CD18 Antigens
-
Intracellular Signaling Peptides and Proteins
-
Protein Kinase Inhibitors
-
STAT Transcription Factors
-
STAT3 Transcription Factor
-
STAT3 protein, human
-
STAT5 Transcription Factor
-
Protein-Tyrosine Kinases
-
SYK protein, human
-
Syk Kinase