Age-related micro-environmental changes as drivers of clonal hematopoiesis.

PURPOSE OF REVIEW: Both aging and reduced diversity at the hematopoietic stem cells (HSCs) level are ubiquitous. What remains unclear is why some individuals develop clonal hematopoiesis (CH), and why does CH due to specific mutations occur in specific individuals. Much like aging, reduced diversity of HSCs is a complex phenotype shaped by numerous factors (germline & environment). The purpose of the current review is to discuss the role of two other age-related ubiquitous processes that might contribute to the dynamics and characteristics of losing HSC diversity and the evolution of CH. These processes have not been reviewed in depth so far and include the accumulation of fatty bone marrow (FBM), and the decline in sex hormones. RECENT FINDINGS: Interestingly, sex hormone decline can directly shape HSC function, but also reshape the delicate balance of BM supporting cells, with a shift towards FBM. FBM accumulation can shape the clonal expansion of preleukemic mutations, particularly DNMT3A mutations, through IL-6 mediation. DNMT3A mutations are one of the only preleukemic mutations which is more prevalent in women, and especially in women with early menopause, demonstrating an association between age-related hormone decline and CH evolution, the mechanisms of which are yet to be discovered. SUMMARY: Aging is a multifactorial phenotype and the same is true for the aging of the blood system. While many factors which can shape CH have been discussed, we shed more light on FBM and sex hormone decline. Much more is missing: how and should we even try to prevent these phenomena? Why do they occur? and how they are connected to other age-related blood factors?

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 (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.