title: PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML.
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.
authors.affiliation: Herman B Wells Center for Pediatric Research.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Goodwin
authors.forename: Xing Jun
authors.initials: XJ
authors.lastname: Li
authors.forename: Raghuveer S
authors.initials: RS
authors.lastname: Mali
authors.forename: Gordon
authors.initials: G
authors.lastname: Chan
authors.forename: Michelle
authors.initials: M
authors.lastname: Kang
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Liu
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lannutti
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Chan
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11