The STAT3-MYC axis promotes survival of leukemia stem cells by regulating SLC1A5 and oxidative phosphorylation
The STAT3-MYC axis promotes survival of leukemia stem cells by regulating SLC1A5 and oxidative phosphorylation
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DOI：
10.1182/blood.2021013201
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发表时间：
2022-01-27
期刊：
影响因子：
20.3
通讯作者：
Jordan, Craig T.
中科院分区：
文献类型：
--
作者：
Amaya, Maria L.;Inguva, Anagha;Jordan, Craig T.
急性髓性白血病（AML）的特征在于存在白血病干细胞（LSC），并且未能完全根除该群体有助于疾病持续/复发。先前的研究已经表征了LSC的代谢脆弱性，其表现出对氧化磷酸化（OXPHOS）的能量代谢和存活的优先依赖。在本研究中，使用遗传学和药理学策略在原发性人类AML标本中，我们表明信号转导子和转录激活子3（STAT 3）介导LSC中的OXPHOS。STAT 3调节AML特异性MYC表达，MYC反过来控制中性氨基酸转运蛋白基因SLC 1A 5的转录。我们表明，MYC或SLC 1A 5的遗传抑制作用表型复制与STAT 3抑制观察到的OXPHOS的损害，从而建立这个轴作为一个调节机制，连接STAT 3的能量代谢。SLC 1A 5的抑制降低谷氨酰胺、谷胱甘肽和多种三羧酸（TCA）循环代谢物的细胞内水平，导致TCA循环活性降低和OXPHOS抑制。基于这些发现，我们使用了一种新的小分子STAT 3抑制剂，它结合STAT 3并破坏STAT 3-DNA，以评估STAT 3的生物学作用。我们表明，STAT 3抑制选择性地导致来自新诊断患者和经历复发的患者的AML干细胞和祖细胞的细胞死亡，同时保留正常的造血细胞。总之，这些发现建立了STAT 3介导的机制，控制原始AML细胞的能量代谢和存活。
Acute myeloid leukemia (AML) is characterized by the presence of leukemia stem cells (LSCs), and failure to fully eradicate this population contributes to disease persistence/ relapse. Prior studies have characterized metabolic vulnerabilities of LSCs, which demonstrate preferential reliance on oxidative phosphorylation (OXPHOS) for energy metabolism and survival. In the present study, using both genetic and pharmacologic strategies in primary human AML specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates OXPHOS in LSCs. STAT3 regulates AML-specific expression of MYC, which in turn controls transcription of the neutral amino acid transporter gene SLC1A5. We show that genetic inhibition of MYC or SLC1A5 acts to phenocopy the impairment of OXPHOS observed with STAT3 inhibition, thereby establishing this axis as a regulatory mechanism linking STAT3 to energy metabolism. Inhibition of SLC1A5 reduces intracellular levels of glutamine, glutathione, and multiple tricarboxylic acid (TCA) cycle metabolites, leading to reduced TCA cycle activity and inhibition of OXPHOS. Based on these findings, we used a novel small molecule STAT3 inhibitor, which binds STAT3 and disrupts STAT3-DNA, to evaluate the biological role of STAT3. We show that STAT3 inhibition selectively leads to cell death in AML stem and progenitor cells derived from newly diagnosed patients and patients who have experienced relapse while sparing normal hematopoietic cells. Together, these findings establish a STAT3-mediated mechanism that controls energy metabolism and survival in primitive AML cells.