| First Author | Goodwin CB | Year | 2014 |
| Journal | Blood | Volume | 123 |
| Issue | 18 | Pages | 2838-42 |
| PubMed ID | 24553178 | Mgi Jnum | J:210890 |
| Mgi Id | MGI:5572849 | Doi | 10.1182/blood-2013-10-535104 |
| Citation | Goodwin CB, et al. (2014) PI3K p110delta uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML. Blood 123(18):2838-42 |
| abstractText | Although hyperactivation of the Ras-Erk signaling pathway is known to underlie the pathogenesis of juvenile myelomonocytic leukemia (JMML), a fatal childhood disease, 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 p110delta, but not PI3K p110alpha, corrects gain-of-function (GOF) Shp2-induced granulocyte macrophage-colony-stimulating factor (GM-CSF) hypersensitivity, Akt and Erk hyperactivation, and skewed hematopoietic progenitor distribution. Likewise, potent p110delta-specific inhibitors curtail the proliferation of GOF Shp2-expressing hematopoietic cells and cooperate with mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK) inhibition to reduce proliferation further and maximally block Erk and Akt activation. Furthermore, the PI3K p110delta-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 p110delta could provide an innovative approach for treatment of JMML, with the potential for limiting toxicity resulting from the hematopoietic-restricted expression of p110delta. |
