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Loss of SHIP and CIS Recruitment to the Granulocyte Colony-Stimulating Factor Receptor Contribute to Hyperproliferative Responses in Severe Congenital Neutropenia/Acute Myelogenous Leukemia¹

Melissa G. Hunter^*, Anand Jacob, Lynn C. O’Donnell^*, Amanda Agler, Lawrence J. Druhan^*, K. Mark Coggeshall and Belinda R. Avalos^2,*

^* Bone Marrow Transplantation Program, The Arthur G. James Cancer Hospital and Richard Solove Research Institute, Department of Molecular Genetics, Ohio State University, Columbus, OH 43210; University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and Department of Immunobiology and Cancer, Oklahoma Medical Research Foundation, Oklahoma City, OK 73014

Mutations in the G-CSF receptor (G-CSFR) in patients with severe congenital neutropenia (SCN) are postulated to contribute to transformation to acute myelogenous leukemia (AML). These mutations result in defective receptor internalization and sustained cellular activation, suggesting a loss of negative signaling by the G-CSFR. In this paper we investigated the roles of SHIP and cytokine-inducible Src homology 2 protein (CIS) in down-modulating G-CSFR signals and demonstrate that loss of their recruitment as a consequence of receptor mutations leads to aberrant signaling. We show that SHIP binds to phosphopeptides corresponding to Tyr⁷⁴⁴ and Tyr⁷⁶⁴ in the G-CSFR and that Tyr⁷⁶⁴ is required for in vivo phosphorylation of SHIP and the formation of SHIP/Shc complexes. Cells expressing a G-CSFR form lacking Tyr⁷⁶⁴ exhibited hypersensitivity to G-CSF and enhanced proliferation, but to a lesser degree than observed with the most common mutant G-CSFR form in patients with SCN/AML, prompting us to investigate whether suppressor of cytokine signaling proteins also down-modulate G-CSFR signals. G-CSF was found to induce the expression of CIS and of CIS bound to phosphopeptides corresponding to Tyr⁷²⁹ and Tyr⁷⁴⁴ of the G-CSFR. The expression of CIS was prolonged in cells with the SCN/AML mutant G-CSFR lacking Tyr⁷²⁹ and Tyr⁷⁴⁴, which also correlated with increased G-CSFR expression. These findings suggest that SHIP and CIS interact with distal phosphotyrosine residues in the G-CSFR to negatively regulate G-CSFR signaling by limiting proliferation and modulating surface expression of the G-CSFR, respectively. Novel therapeutic approaches targeting inhibitory pathways that limit G-CSFR signaling may have promise in the treatment of patients with SCN/AML.

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