Palam, Lakshmi ReddyMali, Raghuveer SinghRamdas, BaskarSrivatsan, Sridhar NonavinkereVisconte, ValeriaTiu, Ramon V.Vanhaesebroeck, BartRoers, AxelGerbaulet, AlexanderXu, MingjiangJanga, Sarath ChandraTakemoto, Clifford M.Paczesny, SophieKapur, Reuben2018-11-192018-11-192018-02-22Palam, L. R., Mali, R. S., Ramdas, B., Srivatsan, S. N., Visconte, V., Tiu, R. V., Vanhaesebroeck, B., Roers, A., Gerbaulet, A., Xu, M., Janga, S. C., Takemoto, C. M., Paczesny, S., … Kapur, R. (2018). Loss of epigenetic regulator TET2 and oncogenic KIT regulate myeloid cell transformation via PI3K pathway. JCI insight, 3(4), e94679. Advance online publication. doi:10.1172/jci.insight.94679https://hdl.handle.net/1805/17788Mutations 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.en-USPublisher PolicyCancerHematologyHematopoietic stem cellsArticle