PI3K p110d uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML.

Blood

PubMedID: 24553178

Goodwin CB, Li XJ, Mali RS, Chan G, Kang M, Liu Z, Vanhaesebroeck B, Neel BG, Loh ML, Lannutti BJ, Kapur R, Chan RJ. PI3K p110d uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML. Blood. 2014;123(18):2838-42.
Although hyperactivation of the Ras-Erk signaling pathway is known to underlie the pathogenesis of the fatal childhood disease, juvenile myelomonocytic leukemia (JMML), the PI3K-Akt signaling pathway is also dysregulated in this disease. Using genetic models, we demonstrate that inactivation of phosphatidylinositol-3-kinase (PI3K) catalytic subunit, p110d, but not PI3K p110a, corrects gain-of-function (GOF) Shp2-induced GM-CSF hypersensitivity, Akt and Erk hyperactivation, and skewed hematopoietic progenitor distribution. Likewise, potent p110d-specific inhibitors curtail the proliferation of GOF Shp2-expressing hematopoietic cells and cooperate with MEK inhibition to reduce proliferation further and maximally block Erk and Akt activation. Furthermore, the PI3K p110d-specific inhibitor, idelalisib, also demonstrates activity against primary leukemia cells from individuals with JMML. These findings suggest that selective inhibition of the PI3K catalytic subunit p110d could provide an innovative approach for treatment of JMML, with the potential for limiting toxicity due to the hematopoietic-restricted expression of p110d.