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Browsing by Author "Vanhaesebroeck, Bart"
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Item Loss of epigenetic regulator TET2 and oncogenic KIT regulate myeloid cell transformation via PI3K pathway(American Society for Clinical Investigation, 2018-02-22) Palam, Lakshmi Reddy; Mali, Raghuveer Singh; Ramdas, Baskar; Srivatsan, Sridhar Nonavinkere; Visconte, Valeria; Tiu, Ramon V.; Vanhaesebroeck, Bart; Roers, Axel; Gerbaulet, Alexander; Xu, Mingjiang; Janga, Sarath Chandra; Takemoto, Clifford M.; Paczesny, Sophie; Kapur, Reuben; Pediatrics, School of MedicineMutations in KIT and TET2 are associated with myeloid malignancies. We show that loss of TET2-induced PI3K activation and -increased proliferation is rescued by targeting the p110α/δ subunits of PI3K. RNA-Seq revealed a hyperactive c-Myc signature in Tet2-/- cells, which is normalized by inhibiting PI3K signaling. Loss of TET2 impairs the maturation of myeloid lineage-derived mast cells by dysregulating the expression of Mitf and Cebpa, which is restored by low-dose ascorbic acid and 5-azacytidine. Utilizing a mouse model in which the loss of TET2 precedes the expression of oncogenic Kit, similar to the human disease, results in the development of a non-mast cell lineage neoplasm (AHNMD), which is responsive to PI3K inhibition. Thus, therapeutic approaches involving hypomethylating agents, ascorbic acid, and isoform-specific PI3K inhibitors are likely to be useful for treating patients with TET2 and KIT mutations.Item PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML(American Society of Hematology, 2014-05-01) 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 J.; Department of Pediatrics, IU School of MedicineAlthough 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.