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 Chan

Research output: Contribution to journalArticle

22 Citations (Scopus)

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

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Juvenile Myelomonocytic Leukemia
Phosphatidylinositol 3-Kinase
Granulocyte-Macrophage Colony-Stimulating Factor
Hypersensitivity
Catalytic Domain
MAP Kinase Kinase Kinases
Genetic Models
Extracellular Signal-Regulated MAP Kinases
Mitogens
Protein Kinases
Toxicity
Leukemia
Chemical activation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML. / Goodwin, Charles B.; Li, Xing Jun; Mali, Raghuveer S.; Chan, Gordon; Kang, Michelle; Liu, Ziyue; Vanhaesebroeck, Bart; Neel, Benjamin G.; Loh, Mignon L.; Lannutti, Brian J.; Kapur, Reuben; Chan, Rebecca.

In: Blood, Vol. 123, No. 18, 01.05.2014, p. 2838-2842.

Research output: Contribution to journalArticle

Goodwin, CB, Li, XJ, Mali, RS, Chan, G, Kang, M, Liu, Z, Vanhaesebroeck, B, Neel, BG, Loh, ML, Lannutti, BJ, Kapur, R & Chan, R 2014, 'PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML', Blood, vol. 123, no. 18, pp. 2838-2842. https://doi.org/10.1182/blood-2013-10-535104
Goodwin, Charles B. ; Li, Xing Jun ; Mali, Raghuveer S. ; Chan, Gordon ; Kang, Michelle ; Liu, Ziyue ; Vanhaesebroeck, Bart ; Neel, Benjamin G. ; Loh, Mignon L. ; Lannutti, Brian J. ; Kapur, Reuben ; Chan, Rebecca. / PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML. In: Blood. 2014 ; Vol. 123, No. 18. pp. 2838-2842.
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