Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis.

Autor: Zioni N; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Bercovich AA; Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel., Chapal-Ilani N; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Bacharach T; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Rappoport N; Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.; Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel., Solomon A; Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel., Avraham R; Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel., Kopitman E; Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Porat Z; Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel., Sacma M; Institute of Molecular Medicine Ulm University, Ulm, Germany., Hartmut G; Institute of Molecular Medicine Ulm University, Ulm, Germany., Scheller M; Department of Medicine, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany., Muller-Tidow C; Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Heidelberg, Heidelberg, Germany., Lipka D; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Heidelberg, Heidelberg, Germany., Shlush E; IVF Unit, Galilee Medical Center, Nahariya, Israel., Minden M; Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.; Department of Medicine, University of Toronto, Toronto, ON, Canada.; Division of Medical Oncology and Hematology, University Health Network, Toronto, ON, Canada.; Division of Hematology, University Health Network, Toronto, ON, Canada., Kaushansky N; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Shlush LI; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. liran.shlush@weizmann.ac.il.; Hematology and Bone Marrow Transplantation Institute Rambam Healthcare campus Haifa, Haifa, Israel. liran.shlush@weizmann.ac.il.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Apr 12; Vol. 14 (1), pp. 2070. Date of Electronic Publication: 2023 Apr 12.
DOI: 10.1038/s41467-023-36906-1
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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