Browsing by Author "Takemoto, Clifford M."

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    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 Medicine
    Mutations 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.