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

Lakshmi Reddy Palam, Raghuveer Singh Mali, Baskar Ramdas, Sridhar Nonavinkere Srivatsan, Valeria Visconte, Ramon V. Tiu, Bart Vanhaesebroeck, Axel Roers, Alexander Gerbaulet, Mingjiang Xu, Sarath Chandra Janga, Clifford M. Takemoto, Sophie Paczesny, Reuben Kapur

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number4
DOIs
StatePublished - Feb 22 2018

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Myeloid Cells
Phosphatidylinositol 3-Kinases
Epigenomics
Ascorbic Acid
Azacitidine
Mutation
Cell Lineage
Mast Cells
Neoplasms
Protein Isoforms
RNA

Keywords

  • Cancer
  • Hematology
  • Hematopoietic stem cells

Cite this

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

In: JCI insight, Vol. 3, No. 4, 22.02.2018.

Research output: Contribution to journalArticle

Palam, LR, Mali, RS, Ramdas, B, Srivatsan, SN, Visconte, V, Tiu, RV, Vanhaesebroeck, B, Roers, A, Gerbaulet, A, Xu, M, Janga, SC, Takemoto, CM, Paczesny, S & Kapur, R 2018, 'Loss of epigenetic regulator TET2 and oncogenic KIT regulate myeloid cell transformation via PI3K pathway', JCI insight, vol. 3, no. 4. https://doi.org/10.1172/jci.insight.94679
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. / Loss of epigenetic regulator TET2 and oncogenic KIT regulate myeloid cell transformation via PI3K pathway. In: JCI insight. 2018 ; Vol. 3, No. 4.
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