miRNA-1 promotes Acute Myeloid Leukemia cell pathogenesis through metabolic regulation [miRNA]

Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by uncontrolled expansion of malignant blasts. The current treatment for AML patients includes intensive chemotherapy and high-risk hematopoietic stem cell transplantation, highlighting the need for less toxic and more effective therapies. Altered metabolism and dysregulated microRNA (miRNA) expression profiles are characteristic of AML. However, there is a paucity of studies exploring how changes in the metabolic state of the leukemic cells regulate miRNA expression leading to altered cellular behavior. Here, we blocked pyruvate entry into mitochondria by deleting the Mitochondria Pyruvate Carrier (MPC1) gene in MV4-11 and Molm-14 human AML cell lines, which decreased Oxidative Phosphorylation (OXPHOS). The loss of MPC1 led to increased expression of miR-1 in both human AML cell lines tested. AML patient sample analysis showed that higher miR-1 expression correlates with reduced survival. Transcriptional and metabolic profiling of miR-1 overexpressing AML cells revealed that miR-1 increased OXPHOS, along with key metabolites that fuel the TCA cycle such as glutamine and fumaric acid. Inhibition of glutaminolysis decreased the elevated OXPHOS in miR-1 overexpressing MV4-11 cells, highlighting that miR-1 regulates OXPHOS through glutaminolysis. Further, the overexpression of miR-1 in AML cells exacerbated disease in a mouse xenograft model. Our work expands current knowledge within the field by uncovering novel connections between AML cell metabolism and miRNA expression that facilitates disease progression. Together, our work points to miR-1 as a potential new therapeutic target that can be used to disrupt AML cell metabolism and thus pathogenesis. Comparison miRNA seq analysis of MV4-11 control and MV4-11 MPC1 KO cells, Molm-14 control and Molm-14 MPC1 KO cells.

急性髓系白血病（Acute myeloid leukemia, AML）是一类异质性且致死性的疾病，以恶性原始细胞失控增殖为核心特征。当前AML患者的治疗手段包括强化化疗与高危造血干细胞移植，凸显了开发低毒高效治疗方案的迫切需求。代谢紊乱与microRNA（miRNA）表达谱失调是AML的典型特征，但目前针对白血病细胞代谢状态变化如何调控miRNA表达、进而改变细胞行为的研究仍较为匮乏。本研究通过在MV4-11与Molm-14两种人AML细胞系中敲除线粒体丙酮酸载体（Mitochondria Pyruvate Carrier, MPC1）基因，阻断丙酮酸进入线粒体，从而降低了氧化磷酸化（Oxidative Phosphorylation, OXPHOS）水平。MPC1缺失可使两种受试人AML细胞系中miR-1的表达均显著上调。对AML患者样本的分析显示，miR-1高表达与患者生存期缩短呈显著相关。对miR-1过表达的AML细胞开展转录组与代谢组分析后发现，miR-1可增强氧化磷酸化水平，同时上调谷氨酰胺、延胡索酸等三羧酸循环供能关键代谢物的丰度。抑制谷氨酰胺分解可降低miR-1过表达MV4-11细胞中升高的氧化磷酸化水平，提示miR-1通过谷氨酰胺分解途径调控氧化磷酸化。进一步的小鼠异种移植模型实验证实，在AML细胞中过表达miR-1可加重疾病进程。本研究揭示了AML细胞代谢与miRNA表达之间的新型关联，该关联可促进疾病进展，拓展了该领域的现有认知。综上，本研究提出miR-1可作为潜在新型治疗靶点，通过干扰AML细胞代谢以阻断其发病机制。本研究对MV4-11对照细胞与MV4-11 MPC1敲除细胞、Molm-14对照细胞与Molm-14 MPC1敲除细胞开展了miRNA测序比较分析。