原点细胞的表观遗传状态定义了白血病的机制
The epigenetic state of the cell of origin defines mechanisms of leukemogenesis
影响因子:13.40000
分区:医学1区 Top / 血液学1区 肿瘤学2区
发表日期:2025 Jan
作者:
Zhiheng Li, Sara Fierstein, Mayuri Tanaka-Yano, Katie Frenis, Chun-Chin Chen, Dahai Wang, Marcelo Falchetti, Parker Côté, Christina Curran, Kate Lu, Tianxin Liu, Stuart Orkin, Hojun Li, Edroaldo Lummertz da Rocha, Shaoyan Hu, Qian Zhu, R Grant Rowe
摘要
急性髓样白血病（AML）显示出可变的临床结果。起源的正常造血细胞影响AML的临床行为，造血干细胞（HSC）的AML容易受到模型系统中化学疗法的耐药性。但是，尚不清楚将HSC程序传输到AML的机制。在这里，我们将白血病MLL-AF9易位引入定义的人类造血种群，发现与祖细胞的AML相比，HSC的AML富含白血病干细胞（LSC）。通过表观遗传分析，我们从正常的HSC中确定了一个推定的继承程序，该程序与Oncogene驱动的程序合作，以赋予HSC-AML的侵略性行为。我们发现，该程序的组成部分是HSC-AML生长和生存所必需的，并确定RNA聚合酶（RNAP）II介导的转录作为治疗脆弱性。总体而言，我们提出了一种机制，即如何通过转化来遗传产生白血病细胞的表观遗传程序以赋予AML的临床异质性。
Abstract
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.