Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis.
Document Type
Article
Publication Date
12-6-2018
Keywords
JGM
JAX Source
Cell Stem Cell 2018 Dec 6; 23(6):833-849.e5
Volume
23
Issue
6
First Page
833
Last Page
849
ISSN
1875-9777
PMID
30526882
DOI
https://doi.org/10.1016/j.stem.2018.10.013
Abstract
Inflammation is a risk factor for cancer development. Individuals with preleukemic TET2 mutations manifest clonal hematopoiesis and are at a higher risk of developing leukemia. How inflammatory signals influence the survival of preleukemic hematopoietic stem and progenitor cells (HSPCs) is unclear. We show a rapid increase in the frequency and absolute number of Tet2-KO mature myeloid cells and HSPCs in response to inflammatory stress, which results in enhanced production of inflammatory cytokines, including interleukin-6 (IL-6), and resistance to apoptosis. IL-6 induces hyperactivation of the Shp2-Stat3 signaling axis, resulting in increased expression of a novel anti-apoptotic long non-coding RNA (lncRNAs), Morrbid, in Tet2-KO myeloid cells and HSPCs. Expression of activated Shp2 in HSPCs phenocopies Tet2 loss with regard to hyperactivation of Stat3 and Morrbid. In vivo, pharmacologic inhibition of Shp2 or Stat3 or genetic loss of Morrbid in Tet2 mutant mice rescues inflammatory-stress-induced abnormalities in HSPCs and mature myeloid cells, including clonal hematopoiesis.
Recommended Citation
Cai Z,
Kotzin J,
Ramdas B,
Chen S,
Nelanuthala S,
Palam L,
Pandey R,
Mali R,
Liu Y,
Kelley M,
Sandusky G,
Mohseni M,
Williams A,
Henao-Mejia J,
Kapur R.
Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis. Cell Stem Cell 2018 Dec 6; 23(6):833-849.e5