复发/难治性急性淋巴细胞白血病（ALL）的生存率仍然很低。我们和其他人已经报道了ALL细胞对通过AMP激活蛋白激酶（AMPK）介导的能量/内质网应激条件的敏感性。为了确定由AMPKα2直接调控的靶基因，我们在正常和能量/代谢应激条件下，在表达HA-AMPKα2（CN2）的CCRF-CEM（T-ALL）细胞中进行了全基因组RNA-seq和ChIP-seq。CN2细胞在代谢应激条件下显示出明显改变的AMPKα2基因组结合和转录组表达谱，包括降低的组蛋白基因表达。蛋白质组学分析和体外激酶测定确定了TATA-盒结合蛋白相关因子1（TAF1）作为一个新的AMPKα2底物，该底物在能量/代谢应激条件下下调组蛋白基因转录。沉默和敲除研究表明，AMPKα2和TAF1都是组蛋白基因表达所需的。机制上，激活后，AMPKα2在Ser-1353位点磷酸化TAF1，从而阻碍TAF1与RNA聚合酶II（Pol II）的相互作用，导致p-AMPKα2/p-TAF1/Pol II染色质结合状态受损，从而抑制转录。这一机制也在原发性ALL细胞和NSG小鼠体内观察到。因此，我们发现了AMPK的非经典功能，即磷酸化TAF1，这两者都是一个被推测与染色质相关的转录复合物的成员，调控组蛋白基因表达等。意义：全面勾画AMPK调控适应性生存反应的蛋白质相互作用组，无论是通过表观遗传基因调控还是其他机制，将有助于理性开发克服ALL和其他癌症中的新生或获得性耐药性的策略。

The survival rates for relapsed/refractory acute lymphoblastic leukemia (ALL) remain poor. We and others have reported that ALL cells are vulnerable to conditions inducing energy/ER-stress mediated by AMP-activated protein kinase (AMPK). To identify the target genes directly regulated by AMPKα2, we performed genome-wide RNA-seq and ChIP-seq in CCRF-CEM (T-ALL) cells expressing HA-AMPKα2 (CN2) under normal and energy/metabolic stress conditions. CN2 cells show significantly altered AMPKα2 genomic binding and transcriptomic profile under metabolic stress conditions, including reduced histone gene expression. Proteomic analysis and in vitro kinase assays identified the TATA-Box Binding Protein Associated Factor 1 (TAF1) as a novel AMPKα2 substrate that downregulates histone gene transcription in response to energy/metabolic stress. Knockdown and knockout studies have demonstrated that both AMPKα2 and TAF1 are required for histone gene expression. Mechanistically, upon activation, AMPKα2 phosphorylates TAF1 at Ser-1353 which impairs TAF1 interaction with RNA polymerase II (Pol II), leading to a compromised state of p-AMPKα2/p-TAF1/Pol II chromatin association and suppression of transcription. This mechanism has also been observed in primary ALL cells and in vivo in NSG mice. Consequently, we uncovered a non-canonical function of AMPK that phosphorylates TAF1, both members of a putative chromatin-associated transcription complex that regulate histone gene expression, among others, in response to energy/metabolic stress. Implications: Fully delineating the protein interactome by which AMPK regulates adaptive survival responses to energy/metabolic stress, either via epigenetic gene regulation or other mechanisms, will allow the rational development of strategies to overcome de novo or acquired resistance in ALL and other cancers.