Many human cancers, including acute myeloid leukemia (AML), arise from mutations of stem and progenitor cells. Immunophenotypic profiling has shown that leukemias develop hierarchically, with mutations in leukemia stem cells associated with disease propagation and relapse1,2. Although leukemia initiating cells can be enriched using cell surface markers, their frequency tends to be variable and low, obscuring mechanisms and hindering effective therapies3,4. To define AML stem cells in human patients, we performed functional genomic profiling of diverse leukemias using label tracing techniques designed to preserve hematopoietic stem cell (HSC) function in vivo. We found that propagation of human AML is mediated by a rare but distinct quiescent label-retaining cell (LRC) population that evades detection by currently known immunophenotypic markers. We show that human AML LRC quiescence is reversible, sparing genetic clonal competition that maintains its epigenetic inheritance. LRC quiescence is defined by distinct promoter-centered chromatin and gene expression dynamics and controlled by a distinct AP-1/ETS transcription factor network, including JUN in particular, which is associated with disease persistence and chemotherapy resistance in diverse patients. These results enable prospective isolation and functional genetic manipulation of immunophenotypically-varied leukemia stem cells in human patient specimens, as well as establish key functions of epigenetic plasticity in leukemia development and therapy resistance. We anticipate that these findings will lead to the elucidation of essential properties of leukemia stem cell quiescence and the design of therapeutic strategies for their clinical identification and control.

中文翻译：

---

控制人类白血病干细胞和治疗耐药的表观遗传机制


许多人类癌症，包括急性髓系白血病 (AML)，都是由干细胞和祖细胞的突变引起的。免疫表型分析表明白血病是分层发展的，白血病干细胞的突变与疾病传播和复发相关1,2。尽管可以使用细胞表面标志物富集白血病起始细胞，但它们的频率往往是可变的且较低，从而模糊了机制并阻碍了有效的治疗3,4。为了定义人类患者的 AML 干细胞，我们使用旨在保护体内造血干细胞 (HSC) 功能的标签追踪技术对多种白血病进行了功能基因组分析。我们发现人类 AML 的传播是由一种罕见但独特的静态标记保留细胞 (LRC) 群体介导的，该群体可以逃避目前已知的免疫表型标记物的检测。我们证明人类 AML LRC 静止是可逆的，避免了维持其表观遗传的遗传克隆竞争。 LRC 静止是由不同的以启动子为中心的染色质和基因表达动力学定义的，并由不同的 AP-1/ETS 转录因子网络控制，特别是 JUN，它与不同患者的疾病持续性和化疗耐药性相关。这些结果使得能够对人类患者标本中免疫表型变异的白血病干细胞进行前瞻性分离和功能性遗传操作，并建立表观遗传可塑性在白血病发展和治疗耐药性中的关键功能。我们预计这些发现将有助于阐明白血病干细胞静止的基本特性，并设计其临床识别和控制的治疗策略。