Journal
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
Volume 97, Issue 7, Pages 1042-1047Publisher
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2011.046896
Keywords
juvenile myelomonocytic leukemia; granulocyte macropage colony stimulating factor; phosphoinositide 3-kinase; PTPN11
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Funding
- Riley Children's Foundation
- U.S. National Institutes of Health [F30 HL104867, HL082981, HL092524]
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Juvenile myelomonocytic leukemia is a lethal disease of children characterized by hypersensitivity of hematopoietic progenitors to granulocyte macrophage-colony stimulating factor. Mutations in PTPN11, the gene encoding the protein tyrosine phosphatase Shp2, are common in juvenile myelomonocytic leukemia and induce hyperactivation of the phosphoinositide-3-kinase pathway. We found that genetic disruption of Pik3r1, the gene encoding the Class IA phosphoinositide-3-kinase regulatory subunits p85 alpha, p55 alpha and p50 alpha, significantly reduced hyperproliferation and hyperphosphorylation of Akt in gain-of-function Shp2 E76K-expressing cells. Elevated protein levels of the phosphoinositide-3-kinase catalytic subunit, p110 delta, in the Shp2 E76K-expressing Pik3r1-/- cells suggest that p110 delta may be a crucial mediator of mutant Shp2-induced phosphoinositide-3-kinase hyperactivation. Consistently, treatment with the p110 delta-specific inhibitor, IC87114, or the clinical grade pan-phosphoinositide-3-kinase inhibitor, GDC-0941, reduced granulocyte macrophage-colony stimulating factor hypersensitivity. Treatment with the farnesyltransferase inhibitor, tipifarnib, showed that Shp2 E76K induces hyperactivation of phosphoinositide-3-kinase by both Ras-dependent and Ras-independent mechanisms. Collectively, these findings implicate Class IA phosphoinositide-3-kinase as a relevant molecular target in juvenile myelomonocytic leukemia.
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