PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML

Charles B. Goodwin, Xing Jun Li, Raghuveer S. Mali, Gordon Chan, Michelle Kang, Ziyue Liu, Bart Vanhaesebroeck, Benjamin G. Neel, Mignon L. Loh, Brian J. Lannutti, Reuben Kapur, Rebecca J. Chan

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24 Scopus citations

Abstract

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 p110δ, but not PI3K p110α, 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 p110δ-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 p110δ-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 p110δ could provide an innovative approach for treatment of JMML, with the potential for limiting toxicity resulting from the hematopoietic-restricted expression of p110δ.

Original languageEnglish (US)
Pages (from-to)2838-2842
Number of pages5
JournalBlood
Volume123
Issue number18
DOIs
StatePublished - May 1 2014

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Goodwin, C. B., Li, X. J., Mali, R. S., Chan, G., Kang, M., Liu, Z., Vanhaesebroeck, B., Neel, B. G., Loh, M. L., Lannutti, B. J., Kapur, R., & Chan, R. J. (2014). PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML. Blood, 123(18), 2838-2842. https://doi.org/10.1182/blood-2013-10-535104