Abstract
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 p85α, p55α and p50α, 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, p110δ, in the Shp2 E76K-expressing Pik3r1-/- cells suggest that p110δ may be a crucial mediator of mutant Shp2-induced phosphoinositide-3-kinase hyperactivation. Consistently, treatment with the p110δ-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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Child
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Class Ia Phosphatidylinositol 3-Kinase / deficiency
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Class Ia Phosphatidylinositol 3-Kinase / genetics*
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / genetics
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Farnesyltranstransferase / antagonists & inhibitors
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Farnesyltranstransferase / genetics
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Gene Expression / drug effects
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
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Humans
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Leukemia, Myelomonocytic, Juvenile / drug therapy
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Leukemia, Myelomonocytic, Juvenile / genetics
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Leukemia, Myelomonocytic, Juvenile / metabolism
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Mice
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Mutation
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics
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Signal Transduction / drug effects
Substances
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Granulocyte-Macrophage Colony-Stimulating Factor
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Farnesyltranstransferase
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Class Ia Phosphatidylinositol 3-Kinase
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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PTPN11 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11