急性髓系白血病 (AML) 的临床结果各不相同。正常造血细胞起源影响 AML 的临床行为，来自造血干细胞 (HSC) 的 AML 在模型系统中容易出现化疗耐药性。然而，HSC 程序传输至 AML 的机制尚不清楚。在这里，我们将致白血病 MLL-AF9 易位引入特定的人类造血群体，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)。通过表观遗传分析，我们从正常 HSC 中识别出一个假定的遗传程序，该程序与癌基因驱动的程序协作，在 HSC-AML 中赋予攻击行为。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脆弱性。总体而言，我们提出了一种机制，说明白血病细胞起源的表观遗传程序如何通过转化遗传，从而赋予 AML 的临床异质性。© 2024。作者，获得 Springer Nature Limited 的独家许可。

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.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.