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Cell Stem Cell. 2018 Dec 6;23(6):833-849.e5. doi: 10.1016/j.stem.2018.10.013.

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

Author information

1
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: zcai@iupui.edu.
2
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
4
Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
5
Lab Head Oncology, Novartis Institutes of Biomedical Research, Cambridge, MA, USA.
6
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; Department of Genetics and Genomic Sciences, University of Connecticut Health Center, Farmington, CT 06032, USA.
7
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
8
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: rkapur@iupui.edu.

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.

KEYWORDS:

Morrbid; Tet2; inflammation; preleukemic; stem cells

PMID:
30526882
PMCID:
PMC6317370
[Available on 2019-12-06]
DOI:
10.1016/j.stem.2018.10.013

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