Journal
CELL STEM CELL
Volume 23, Issue 6, Pages 833-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2018.10.013
Keywords
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Categories
Funding
- NIH [R01HL077177, R01CA173852, R01CA134777, T32HL007910, R01 CA167291, R21AI128060, R21DK111755, R01HL136572]
- Leukemia and Lymphoma Society
- Riley Children's Foundation
- PEW Charitable Foundation
- Burroughs Welcome Fund
- NATIONAL CANCER INSTITUTE [R01CA167291, R01CA134777, R01CA173852] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL007910, R01HL077177, R01HL140961, R01HL136572, R01HL146137] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R21AI128060] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R21DK111755, T32DK007780, U54DK106846] Funding Source: NIH RePORTER
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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 (IncRNAs), 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.
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