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Cited by 67Acute Myeloid Leukemia ResearchHematopoietic Stem Cell TransplantationMesenchymal stem cell research

Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis

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Zioni, N., Bercovich, A. Akhiad, Chapal-Ilani, N., Bacharach, Tal, Rappoport, N., Solomon, A., Avraham, R., Kopitman, E. +10 more·2023·Nature Communications
DOI 10.1038/s41467-023-36906-1PMC PMC10097668

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Abstract

Both fatty bone marrow (FBM) and somatic mutations in hematopoietic stem cells (HSCs), also termed clonal hematopoiesis (CH) accumulate with human aging. However it remains unclear whether FBM can modify the evolution of CH. To address this question, we herein present the interaction between CH and FBM in two preclinical male mouse models: after sub-lethal irradiation or after castration. An adipogenesis inhibitor (PPARγ inhibitor) is used in both models as a control. A significant increase in self-renewal can be detected in both human and rodent DNMT3A Mut -HSCs when exposed to FBM. DNMT3A Mut -HSCs derived from older mice interacting with FBM have even higher self-renewal in comparison to DNMT3A Mut -HSCs derived from younger mice. Single cell RNA-sequencing on rodent HSCs after exposing them to FBM reveal a 6-10 fold increase in DNMT3A Mut -HSCs and an activated inflammatory signaling. Cytokine analysis of BM fluid and BM derived adipocytes grown in vitro demonstrates an increased IL-6 levels under FBM conditions. Anti-IL-6 neutralizing antibodies significantly reduce the selective advantage of DNMT3A Mut -HSCs exposed to FBM. Overall, paracrine FBM inflammatory signals promote DNMT3A -driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 pathway.

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  • Ccl5 encodes a chemokine that acts on immune cells and neurons and has been associated with brain pathologies, including PD.

    “Interestingly though, in particular the MoMg derived from hDNMT3A R882H HSC also prominently expressed Ccl5 , encoding a chemokine that acts on immune cells and neurons, and has been associated with brain pathologies, including PD 53-55 .”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [54]

    The Introduction and Discussion discuss inflammatory signals from fatty bone marrow, particularly IL-6, but do not address Ccl5’s effects on immune cells or neurons or its association with Parkinson’s disease. Searches of our copy for Ccl5, neurons, and Parkinson’s disease found no passage supporting the attributed claim. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • hDNMT3A R882H monocyte-derived microglia expressed significant levels of Ccl5.

    “Notably, hDNMT3A R882H MoMg also expressed significant levels of Ccl5 , a chemokine that has been associated with brain pathologies and was shown to act on immune cells and neurons 53-55 .”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [54]

    The Results passages on human DNMT3A R882H cells concern bone-marrow HSPCs and engraftment, not monocyte-derived microglia. Searches for Ccl5, microglia, and the hDNMT3A R882H combination found no passage reporting the claimed expression; page numbers were unavailable in our copy. (LLM, conf=0.76)

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Cited by

Sorted by citations

Authors
Zioni, N., Bercovich, A. A., Chapal-Ilani, N., Bacharach, T., Rappoport, N., Solomon, A., Avraham, R., Kopitman, E., Porat, Z., Sacma, M., Hartmut, G., Scheller, M., Muller-Tidow, C., Lipka, D., Shlush, E., Minden, M., Kaushansky, N., & Shlush, L. I.
Affiliations
  • Weizmann Institute of Science (IL)
  • Tel Aviv University (IL)
  • University Hospital Heidelberg (DE)
  • German Cancer Research Center (DE)
  • Western Galilee Hospital (IL)
  • University Health Network (CA)
  • Rambam Health Care Campus (IL)
Corresponding author
Shlush, Liran I.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-04-12
Volume
14
Issue
1
Pages
2070-2070
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-36906-1
PMC
PMC10097668
OpenAlex
W4365145093
Cited by
67
References
18
Citations by year
2026: 18 · 2025: 20 · 2024: 19 · 2023: 10
FWCI
13.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Applebaum Foundation
  • National Natural Science Foundation of China
  • Israel Science Foundation (2427/18, 3165 / 19)
  • Rising Tide Foundation (RTF6005-19)
  • BIRAX
  • H2020 European Research Council (714731)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
clonal hematopoiesis, DNMT3A mutation, hematopoietic stem cells, aging, adipose tissue inflammation, IL-6 signaling, paracrine signaling, stem cell self-renewal, castration, irradiation, adipogenesis, somatic mutations
MeSH terms
Clonal Hematopoiesis, DNA Methyltransferase 3A, Animals, Bone Marrow, DNA (Cytosine-5-)-Methyltransferases, Hematopoiesis, Humans, Male, Mice

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