Genetic disruption of the PI3K regulatory subunits, p85α, p55α, and p50α, normalizes mutant PTPN11-induced hypersensitivity to GM-CSF

• Published in: Haematologica (Roma) Vol. 97; no. 7; pp. 1042 - 1047
• Main Authors: GOODWIN, Charles B, ZHENYUNYANG, FUQIN YIN, MENGGANGYU, CHAN, Rebecca J
• Format: Journal Article
• Language: English
• Published: Pavia Ferrata Storti Foundation 01-07-2012
• Subjects: Animals; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Child; Class Ia Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Class Ia Phosphatidylinositol 3-Kinase - deficiency; Class Ia Phosphatidylinositol 3-Kinase - genetics; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - genetics; Farnesyltranstransferase - antagonists & inhibitors; Farnesyltranstransferase - genetics; Gene Expression - drug effects; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Hematologic and hematopoietic diseases; Humans; Leukemia, Myelomonocytic, Juvenile - drug therapy; Leukemia, Myelomonocytic, Juvenile - genetics; Leukemia, Myelomonocytic, Juvenile - metabolism; Medical sciences; Mice; Mutation; Original and Brief Reports; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - genetics; Signal Transduction - drug effects; PTPN11 gene; Hematology; Enzyme; Transferases; Hypersensitivity; PTPN11; Regulatory subunit; 1-Phosphatidylinositol 3-kinase; Granulocyte colony stimulating factor; Genetics; Juvenile myelomonocytic leukemia; Mutation; granulocyte macropage colony stimulating factor; Granulocyte macrophage colony stimulating factor; phosphoinositide 3-kinase
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2011.046896

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.