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Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis

Author

Listed:
  • N. Zioni

    (Weizmann Institute of Science)

  • A. Akhiad Bercovich

    (Weizmann Institute of Science)

  • N. Chapal-Ilani

    (Weizmann Institute of Science)

  • Tal Bacharach

    (Weizmann Institute of Science)

  • N. Rappoport

    (Weizmann Institute of Science
    Tel Aviv University)

  • A. Solomon

    (Weizmann Institute of Science)

  • R. Avraham

    (Weizmann Institute of Science)

  • E. Kopitman

    (Weizmann Institute of Science)

  • Z. Porat

    (Weizmann Institute of Science)

  • M. Sacma

    (Institute of Molecular Medicine Ulm University)

  • G. Hartmut

    (Institute of Molecular Medicine Ulm University)

  • M. Scheller

    (University Hospital Heidelberg)

  • C. Muller-Tidow

    (Heidelberg University Hospital
    European Molecular Biology Laboratory (EMBL)
    Partner Site Heidelberg)

  • D. Lipka

    (Partner Site Heidelberg)

  • E. Shlush

    (Galilee Medical Center)

  • M. Minden

    (University Health Network (UHN)
    University of Toronto
    University of Toronto
    University Health Network)

  • N. Kaushansky

    (Weizmann Institute of Science)

  • Liran I. Shlush

    (Weizmann Institute of Science
    Hematology and Bone Marrow Transplantation Institute Rambam Healthcare campus Haifa)

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 DNMT3AMut-HSCs when exposed to FBM. DNMT3AMut-HSCs derived from older mice interacting with FBM have even higher self-renewal in comparison to DNMT3AMut-HSCs derived from younger mice. Single cell RNA-sequencing on rodent HSCs after exposing them to FBM reveal a 6-10 fold increase in DNMT3AMut-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 DNMT3AMut-HSCs exposed to FBM. Overall, paracrine FBM inflammatory signals promote DNMT3A-driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 pathway.

Suggested Citation

  • N. Zioni & A. Akhiad Bercovich & N. Chapal-Ilani & Tal Bacharach & N. Rappoport & A. Solomon & R. Avraham & E. Kopitman & Z. Porat & M. Sacma & G. Hartmut & M. Scheller & C. Muller-Tidow & D. Lipka & , 2023. "Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36906-1
    DOI: 10.1038/s41467-023-36906-1
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    as
    1. Liran I. Shlush & Amanda Mitchell & Lawrence Heisler & Sagi Abelson & Stanley W. K. Ng & Aaron Trotman-Grant & Jessie J. F. Medeiros & Abilasha Rao-Bhatia & Ivana Jaciw-Zurakowsky & Rene Marke & Jessi, 2017. "Tracing the origins of relapse in acute myeloid leukaemia to stem cells," Nature, Nature, vol. 547(7661), pages 104-108, July.
    2. Erica L. Scheller & Casey R. Doucette & Brian S. Learman & William P. Cawthorn & Shaima Khandaker & Benjamin Schell & Brent Wu & Shi-Ying Ding & Miriam A. Bredella & Pouneh K. Fazeli & Basma Khoury & , 2015. "Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    3. Sagi Abelson & Grace Collord & Stanley W. K. Ng & Omer Weissbrod & Netta Mendelson Cohen & Elisabeth Niemeyer & Noam Barda & Philip C. Zuzarte & Lawrence Heisler & Yogi Sundaravadanam & Robert Luben &, 2018. "Prediction of acute myeloid leukaemia risk in healthy individuals," Nature, Nature, vol. 559(7714), pages 400-404, July.
    4. Olaia Naveiras & Valentina Nardi & Pamela L. Wenzel & Peter V. Hauschka & Frederic Fahey & George Q. Daley, 2009. "Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment," Nature, Nature, vol. 460(7252), pages 259-263, July.
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