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Cited by 394Acute Myeloid Leukemia ResearchHematopoietic Stem Cell TransplantationProtein Tyrosine Phosphatases

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

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Cai, Zhigang, Kotzin, Jonathan J., Ramdas, Baskar, Chen, Sisi, Nelanuthala, Sai, Palam, Lakshmi Reddy, Pandey, Ruchi, Mali, Raghuveer Singh +7 more·2018·Cell Stem Cell
DOI 10.1016/j.stem.2018.10.013PMC PMC6317370
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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.

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  • Chemical inhibitors of NF-κB and STAT3 (E3330), or SHP2 (SHP099), abrogate the competitive growth of aged Tet2−/− cells.

    “The authors then blocked the pathways with chemical inhibitors of both NF-κB and STAT3 (E3330), or SHP2 (SHP099), and showed that either of these compounds abrogates the competitive growth of aged Tet2−/− cells and reduces serum IL-6 levels [82].”

    From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [82]

    The Results section reports that E3330 and SHP099 significantly repressed Tet2-KO cell expansion relative to wild-type cells in chimeric mice. It separately reports improved blood counts and reduced serum IL-6 in aged Tet2-KO mice, but does not show that either drug abrogated competitive growth specifically in aged Tet2-KO cells. No page number is available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Tet2-deficient HSPCs maintain a repopulation advantage after exposure to bacterial lipopolysaccharides due to increased resistance to IL-6-mediated apoptosis.

    “Moreover, Tet2-deficient HSPCs maintain a repopulation advantage after exposure to bacterial lipopolysaccharides (LPSs), due to increased resistance to IL-6–mediated apoptosis,16”

    From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [16]

    The Results section on repopulating activity (page unavailable) reports that Tet2-KO HSPCs maintain greater engraftment than wild-type cells after LPS challenge; the apoptosis Results section reports less apoptosis in Tet2-KO cells after LPS. But the IL-6 experiments report reduced apoptosis of Tet2-KO cells in the presence of IL-6, not resistance to apoptosis mediated by IL-6. The claim’s proposed mechanism therefore misstates what the paper shows. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Most CHIP mouse models rely on BM transplantation following high-dose irradiation and inevitably increased inflammatory milieus.

    “Currently, most CHIP mouse models rely on BM transplantation following high-dose irradiation and inevitably increased inflammatory milieus.16,24,39”

    From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [16]

    The STAR*METHODS Method Details section (page not supplied) says this paper’s bone-marrow transplantation recipients were lethally irradiated before transplantation, supporting the claim for this model. The paper does not establish that most CHIP mouse models use this approach or that irradiation inevitably increases the inflammatory milieu. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Chemical inhibitors of NF-κB and STAT3 (E3330), or SHP2 (SHP099), reduce serum IL-6 levels.

    “The authors then blocked the pathways with chemical inhibitors of both NF-κB and STAT3 (E3330), or SHP2 (SHP099), and showed that either of these compounds abrogates the competitive growth of aged Tet2−/− cells and reduces serum IL-6 levels [82].”

    From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [82]

  • An antiapoptotic long non-coding RNA called Morrbid mediates downregulation of Bim, downstream of a hyperactivated SHP2-STAT3 signaling axis in Tet2−/− HSPCs.

    “Complementary work explored the mechanism behind this phenotype and identified an antiapoptotic long non-coding RNA called Morrbid that mediates downregulation of Bim, downstream of a hyperactivated SHP2–STAT3 signaling axis in Tet2−/− HSPCs [82].”

    From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [82]

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Cited by

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Authors
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.
Affiliations
  • Indiana University Indianapolis (US)
  • University of Pennsylvania (US)
  • Indiana University School of Medicine (US)
  • The Jackson Laboratory for Genomic Medicine (US)
Corresponding author
  • Cai, Zhigang
  • Kapur, Reuben
ORCID
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2018-12
Volume
23
Issue
6
Pages
833-849.e5
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2018.10.013
PMC
PMC6317370
OpenAlex
W2905501602
Cited by
394
References
11
Citations by year
2026: 50 · 2025: 57 · 2024: 59 · 2023: 53 · 2022: 66 · 2021: 42 · 2020: 47 · 2019: 20
FWCI
19.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • Purdue University Indianapolis (Indiana University) (submittedVersion)
Funders
  • NIH (R01HL077177, R01CA173852, R01CA134777, T32HL007910, R01 CA167291, R01HL136572)
  • Leukemia and Lymphoma Society
  • Riley Children’s Foundation
  • PEW Charitable Foundation (R21AI128060)
  • Burroughs Welcome Fund (R21DK111755)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
TET2 mutation, preleukemic cells, clonal hematopoiesis, inflammation, inflammatory stress, hematopoietic stem and progenitor cells, myeloid cells, interleukin-6, long non-coding RNA, apoptosis resistance, leukemia risk
MeSH terms
Animals, DNA-Binding Proteins, Female, Hematopoiesis, Hematopoietic Stem Cells, Inflammation, Male, Mice, Inbred C57BL, Mutation, Piperidines, Propionates, Proto-Oncogene Proteins, Pyrimidines, Signal Transduction, Benzoquinones, Mice, Knockout, Oxidative Stress, Myeloid Cells, Dioxygenases, Mice, RNA, Long Noncoding

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