Inflammatory signals from fatty bone marrow support DNMT3a-driven clonal hematopoiesis (Dnmt3A KI heterozygote subset)
Accumulation of fatty bone marrow (FBM) is one of the key age related changes possibly influencing the blood system. While a link between obesity and cancer evolution has been reported it remains unknown whether FBM can modify the evolution of the early stages of leukemia and clonal hematopoiesis (CH). To address this question, we established different FBM mouse models in immunodeficient mice in whom we can study both mouse and human cells. We focused our studies on two FBM models: 1) after sublethal irradiation; 2) after castration; and in both we used an adipogenesis inhibitor as a control (PPAR? inhibitor). We transplanted both human and mice hematopoietic stem cells (HSCs) carrying DNMT3A mutations into immunodeficient mice with FBM. A significant increase in self-renewal was found when DNMT3AMut-HSCs were exposed to FBM. To better understand the mechanisms of the FBM-CH interaction, we performed single cell RNA-sequencing on HSPCs after FBM exposure in vivo. A 6-10 fold increase in DNMT3AMut-HSCs was observed under FBM conditions in comparison to normal bone marrow. Mutated HSCs from mice exposed to FBM exhibited an activated inflammatory signaling (IL-6 and IFN?). Cytokine analysis of BM fluid and BM derived adipocytes grown in vitro demonstrated increased IL-6 levels under FBM conditions. Anti-IL-6 neutralizing antibodies significantly reduced the selective advantage of mice derived DNMT3AMut-HSCs exposed to FBM. Overall, paracrine FBM inflammatory signals promote DNMT3A-driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 receptor.