Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis

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 (PPAR gamma 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.

Automated summary

The accumulation of fatty bone marrow and somatic mutations in hematopoietic stem cells (HSCs) increases with aging. In preclinical mouse models, it is found that fatty bone marrow can enhance the self-renewal of HSCs and activate inflammatory signaling. The inflammatory cytokines, such as IL-6, in fatty bone marrow promote DNMT3a-driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 pathway.