Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis

Zhigang Cai, Jonathan J. Kotzin, Baskar Ramdas, Sisi Chen, Sai Nelanuthala, Lakshmi Reddy Palam, Ruchi Pandey, Raghuveer Singh Mali, Yan Liu, Mark R. Kelley, George Sandusky, Morvarid Mohseni, Adam Williams, Jorge Henao-Mejia, Reuben Kapur

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19 Scopus citations

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. Cai et al. report that Tet2-deficient hematopoietic stem and progenitor cells manifest a hyperactive IL-6/Shp2/Stat3/Morrbid pathway, which promotes cell survival under basal conditions and in response to inflammatory stress. Blocking this pathway using anti-inflammatory drugs (E3330 and SHP099) or by genetic loss of Morrbid mitigates this response.

Original languageEnglish (US)
Pages (from-to)833-849.e5
JournalCell Stem Cell
Volume23
Issue number6
DOIs
StatePublished - Dec 6 2018

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Keywords

  • Morrbid
  • Tet2
  • inflammation
  • preleukemic
  • stem cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Cai, Z., Kotzin, J. J., Ramdas, B., Chen, S., Nelanuthala, S., Palam, L. R., Pandey, R., Mali, R. S., Liu, Y., Kelley, M. R., Sandusky, G., Mohseni, M., Williams, A., Henao-Mejia, J., & Kapur, R. (2018). Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis. Cell Stem Cell, 23(6), 833-849.e5. https://doi.org/10.1016/j.stem.2018.10.013