Sperb Nadine, Maksakova Irina A, Escano Leo, Abraham Libin, MacPhee Liam, Cabantog Ariene, Kim Dexter, Yu Mansen, Krowiorz Kathrin, Im Junbum, Grasedieck Sarah, Pochert Nicole, Ruess Christoph, Rösler Reinhild, Flibotte Stephane, Maetzig Tobias, Calzia Enrico, Palmqvist Lars, Wiese Sebastian, Fogelstrand Linda, Gold Michael R, Rouhi Arefeh, Kuchenbauer Florian
Department of Internal Medicine III, University Hospital Ulm, Ulm, 89081, Germany.
Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
Leukemia. 2025 May;39(5):1090-1101. doi: 10.1038/s41375-025-02558-x. Epub 2025 Mar 17.
We investigated the clinical and functional role of the miR-106a-363 cluster in adult acute myeloid leukemia (AML). LAML miRNA-Seq TCGA analyses revealed that high expression of miR-106a-363 cluster members was associated with inferior survival, and miR-106a-5p and miR-20b-5p levels were significantly elevated in patients with adverse risk AML. Overexpression of the miR-106a-363 cluster and its individual members in a murine AML model significantly accelerated leukemogenesis. Proteomics analysis of leukemic bone marrow cells from these models emphasized the deregulation of proteins involved in intracellular transport, protein complex organization and mitochondrial function, driven predominantly by miR-106a-5p. These molecular alterations suggested mitochondrial activation as a potential mechanism for the observed increase in leukemogenicity. High-resolution respirometry and STED microscopy confirmed that miR-106a-5p enhances mitochondrial respiratory activity and increases mitochondrial volume. These findings demonstrate that the miR-106a-363 cluster, and particularly miR-106a-5p, contribute to AML progression through modulation of mitochondrial function and deregulation of mitochondria-coordinated pathways.
我们研究了miR-106a-363簇在成人急性髓系白血病（AML）中的临床和功能作用。LAML miRNA-Seq TCGA分析显示，miR-106a-363簇成员的高表达与较差的生存率相关，并且在具有不良风险AML的患者中miR-106a-5p和miR-20b-5p水平显著升高。在小鼠AML模型中过表达miR-106a-363簇及其单个成员显著加速了白血病的发生。对这些模型的白血病骨髓细胞进行蛋白质组学分析强调了主要由miR-106a-5p驱动的参与细胞内运输、蛋白质复合物组织和线粒体功能的蛋白质的失调。这些分子改变提示线粒体激活是观察到的白血病发生能力增加的潜在机制。高分辨率呼吸测定法和受激发射损耗显微镜证实miR-106a-5p增强线粒体呼吸活性并增加线粒体体积。这些发现表明，miR-106a-363簇，特别是miR-106a-5p，通过调节线粒体功能和失调线粒体协调途径促进AML进展。
