Cell of origin defines epigenetic mechanisms of transformation

Acute myeloid leukemias (AMLs) show variable clinical outcomes. The differentiation state of the normal hematopoietic cell of origin impacts the behavior of AML, with AML from hematopoietic stem cells (HSCs) prone to chemotherapy resistance in model systems. However, the mechanisms by which HSC programs are transmitted to AML are not known. Here, we introduce a leukemogenic translocation into defined human hematopoietic populations, finding that AMLs from HSCs show the highest stem cell content. By epigenetic profiling, we identify a putative program from the normal HSC that collaborates with oncogene-driven programs to confer exceptional aggressiveness. We confirm that components of this program are required for HSC-AML growth and survival and identify RNA polymerase (RNAP) II-mediated transcription as a therapeutic vulnerability. Overall, we propose a mechanism as to how epigenetic programs from the leukemic cell of origin are inherited through transformation to impact heterogeneity in AML biology.