Loss of epigenetic regulator TET2 and oncogenic KIT regulate myeloid cell transformation via PI3K pathway.

JCI Insight
Lakshmi Reddy PalamReuben Kapur

Abstract

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.

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Citations

Nov 15, 2019·HemaSphere·James Neil FisherJuerg Schwaller
Aug 27, 2019·Environmental Science and Pollution Research International·Aisha Abdullah Mohammed Alayafi
Oct 14, 2020·Cancer Science·Hiroyoshi Kunimoto, Hideaki Nakajima
Mar 25, 2021·The Journal of Experimental Medicine·Lucille StuaniJean-Emmanuel Sarry
Jun 17, 2021·Journal of Cellular and Molecular Medicine·Takuya ShimizuAkifumi Takaori-Kondo

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Methods Mentioned

BETA
flow cytometry
RNA-Seq
transfection
lavage
PCR
dot blot

Software Mentioned

HISAT
R
cytoscape analysis
GSEA
BiQ analyzer
McLab
FastQC
Edge R )
Cytoscape
StringTie

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