Acute myeloid leukemia (AML) shows variable clinical outcome. The normal hematopoietic cell of origin impacts the clinical 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 the leukemogenic MLL-AF9 translocation into defined human hematopoietic populations, finding that AML from HSCs is enriched for leukemic stem cells (LSCs) compared to AML from progenitors. By epigenetic profiling, we identify a putative inherited program from the normal HSC that collaborates with oncogene-driven programs to confer aggressive behavior in HSC-AML. We find 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 impart the clinical heterogeneity of AML.

急性髓系白血病 （AML） 的临床结局各不相同。正常的造血干细胞来源会影响 AML 的临床行为，造血干细胞 （HSC） 的 AML 在模型系统中容易产生化疗耐药性。然而，HSC 程序传播到 AML 的机制尚不清楚。在这里，我们将产白血病 MLL-AF9 易位引入确定的人类造血细胞群，发现与来自祖细胞的 AML 相比，来自 HSC 的 AML 富含白血病干细胞 （LSC）。通过表观遗传学分析，我们确定了来自正常 HSC 的假定遗传程序，该程序与癌基因驱动的程序合作，以赋予 HSC-AML 中的攻击性行为。我们发现该程序的组成部分是 HSC-AML 生长和存活所必需的，并将 RNA 聚合酶 （RNAP） II 介导的转录确定为治疗性漏洞。总体而言，我们提出了一种机制，说明来自白血病起源细胞的表观遗传程序如何通过转化遗传以赋予 AML 的临床异质性。