Age-related clonal hematopoiesis and its link to age-related changes in the bone marrow microenvironment

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Age-related clonal hematopoiesis (ARCH or simply CH) is defined as the gradual, clonal expansion of hematopoietic stem and progenitor cells (HSPCs) carrying specific, disruptive, and recurrent genetic variants, in individuals without clear diagnosis of hematological malignancies. It is becoming clearer that CH is associated with many pathological states and increased risk for blood cancers. One of the environmental factors that may influence CH with age is fatty bone marrow (FBM). At birth the bone marrow (BM) contains functionally active hematopoietic tissue, known as red BM. During aging there is a shift from red marrow to adipocyte-enriched yellow BM. Previous studies suggested that normal HSCs are influenced by the fatty BM microenvironment. Here, we hypothesize that age related bone marrow fat (BMF) accumulation might provide selective advantage to specific pre-leukemic stem and progenitor cells (preL-HSPCs) carrying pre-leukemic mutations (pLM). To support this hypothesis, the Shlush and Geiger laboratories established and validated a FBM model in NSG mice to study both human and murine preL-HSPCs behavior within FBM. Transplantation of primary human preL-HSPCs from an AML patient (DNMT3a, NPM1 mutations) into FBM resulted in enhanced engraftment compared to control mice without FBM. We further demonstrate that R882H+/- mice derived BM HSPCs, engrafted significantly higher in NSG mice with FBM compared to controls. Moreover, ten-fold increase in engraftment of R882H+/- derived BM from aged mice (one year old) was detected when injected into a FBM mice. Notably, no increase in engraftment of Srsf2P95HxVAV derived BM was detected in NSG mice with FBM. These results demonstrate for the first time that the FBM provides a selective advantage to pre-leukemic cells carrying R882H. Remaining unanswered questions are - what are the underlying molecular mechanisms conferring the advantage provided by the FBM specifically to preL-HSPCs carrying DNMT3A in comparison to WT HSPCs? What is the interplay of FBM with preL-HSPCs carrying other mutations, like ASXL1, spliceosome mutations? What is the location of the settled preleukemic cells in BM? What are the effects of FBM on normal hematopoiesis in young and aged mice? This study will be a collaborative effort between two laboratories with a highly complementary expertise. The Geiger lab gained expertise in the aging of rodents HSCs and in changes in the BM microenvironment. The Shlush lab has expertise in human HSC aging, clonal hematopoiesis and xenografts. Studying the interaction between the BM microenvironment and human HSCs demands the combination of expertise of both laboratories.