| First Author | Goodwin CB | Year | 2012 |
| Journal | Haematologica | Volume | 97 |
| Issue | 7 | Pages | 1042-7 |
| PubMed ID | 22315502 | Mgi Jnum | J:316384 |
| Mgi Id | MGI:6835680 | Doi | 10.3324/haematol.2011.046896 |
| Citation | Goodwin CB, et al. (2012) Genetic disruption of the PI3K regulatory subunits, p85alpha, p55alpha, and p50alpha, normalizes mutant PTPN11-induced hypersensitivity to GM-CSF. Haematologica 97(7):1042-7 |
| abstractText | 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 p85alpha, p55alpha and p50alpha, 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, p110delta, in the Shp2 E76K-expressing Pik3r1-/- cells suggest that p110delta may be a crucial mediator of mutant Shp2-induced phosphoinositide-3-kinase hyperactivation. Consistently, treatment with the p110delta-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. |
