Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance
Sumiko Takao, Victor Morell, Masahiro Uni, Alicia Slavit, Sophia Rha, Shuyuan Cheng, Laura K. Schmalbrock, Fiona C. Brown, Sergi Beneyto‐Calabuig, Richard P. Koche, Lars Velten, Alex Kentsis
Abstract
Cancer stem cells are essential for initiation and therapy resistance of many cancers, including acute myeloid leukemias (AML). Here, we apply functional genomic profiling to diverse human leukemias, including high-risk MLL- and NUP98-rearranged specimens, using label tracing in vivo. Human leukemia propagation is mediated by a rare quiescent label-retaining cell (LRC) population undetectable by current immunophenotypic markers. AML quiescence is reversible, preserving genetic clonal competition and epigenetic inheritance. LRC quiescence is defined by distinct promoter-centered chromatin and gene expression dynamics controlled by an AP-1/ETS transcription factor network, where JUN is necessary and sufficient for LRC quiescence and associated with persistence and chemotherapy resistance in diverse patients. This enables prospective isolation and manipulation of immunophenotypically-varied leukemia stem cells, establishing the functions of epigenetic plasticity in leukemia development and therapy resistance. These findings offer insights into leukemia stem cell quiescence and the design of therapeutic strategies for their clinical identification and control. Acute myeloid leukemia (AML) arise from mutations of stem and progenitor cells. Here, authors identify a quiescent, label-retaining cell population in AML patient specimens that have tumor-initiation capacity and unique epigenetic and transcriptional properties that can be functionally altered by expression of transcription factors such as JUN.