AMPK links acetyl-coA homeostasis to BET recruitment in acute myeloid leukemia: RNA-seq. AMPK links acetyl-coA homeostasis to BET recruitment in acute myeloid leukemia: RNA-seq

Altered metabolism fuels two hallmark properties of cancer cells, unlimited proliferation and differentiation blockade. AMP-activated protein kinase (AMPK) is a master regulator of bioenergetics crucial for glucose metabolism in acute myeloid leukemia (AML) and its inhibition delays leukemogenesis, but whether the metabolic function of AMPK alters AML epigenome remains unknown. Here, we demonstrate that AMPK maintains the epigenome of MLL-rearranged AML by linking acetyl-CoA homeostasis to BET bromodomain protein recruitment to chromatin. AMPK deletion reduced acetyl-CoA and histone acetylation, displacing BET proteins from chromatin in leukemia-initiating cells (LICs). In both mouse and patient-derived xenograft AML models, treating with AMPK and BET inhibitors synergistically suppressed AML. Our results provide a therapeutic rationale to target AMPK and BET for AML therapy. Overall design: RNA-seq of sorted AMPK WT or KO leukemia-GMP cells, with three replicates of each.

代谢重编程为癌细胞的两大标志性特征提供能量支撑：无限增殖与分化阻滞。腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK）是急性髓系白血病（acute myeloid leukemia, AML）糖代谢关键的能量稳态主控调节因子，抑制AMPK可延缓白血病发生，但AMPK的代谢功能是否会改变AML的表观基因组，目前仍不明确。本研究证实，AMPK可通过将乙酰辅酶A稳态与BET溴结构域蛋白向染色质的招募过程相耦联，维持MLL重排型急性髓系白血病的表观基因组稳态。在白血病起始细胞（leukemia-initiating cells, LICs）中，AMPK敲除会降低乙酰辅酶A水平与组蛋白乙酰化程度，促使BET蛋白从染色质上解离。在小鼠模型与患者来源异种移植AML模型中，联合使用AMPK抑制剂与BET抑制剂可协同抑制AML进展。本研究结果为靶向AMPK与BET靶点治疗AML提供了理论依据。实验设计概述：对分选得到的AMPK野生型（WT）或敲除型（KO）白血病粒细胞-巨噬细胞系祖细胞（leukemia-GMP cells）进行RNA测序，每组设置3次生物学重复。