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Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis
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Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis
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Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis
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Journal Article
Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis
2023
Overview
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.
Age related accumulation of adipocytes in the bone marrow could alter normal and leukemic haematopoiesis. Here, in fatty bone marrow (FBM) preclinical models, the authors show that inflammatory cytokines increased in the FBM, such as IL-6, promote DNMT3a driven clonal hematopoiesis.
