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

Date
2018-02-22
Language
American English
Embargo Lift Date
Committee Members
Degree
Degree Year
Department
Grantor
Journal Title
Journal ISSN
Volume Title
Found At
American Society for Clinical Investigation
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.

Description
item.page.description.tableofcontents
item.page.relation.haspart
Cite As
Palam, 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.94679
ISSN
Publisher
Series/Report
Sponsorship
Major
Extent
Identifier
Relation
Journal
JCI insight
Rights
Publisher Policy
Source
PMC
Alternative Title
Type
Article
Number
Volume
Conference Dates
Conference Host
Conference Location
Conference Name
Conference Panel
Conference Secretariat Location
Version
Final published version
This item is under embargo {{howLong}}