Li-Harms Xiujie, Lu Jingjun, Fukuda Yu, Lynch John, Sheth Aditya, Pareek Gautam, Kaminski Marcin M, Ross Hailey S, Wright Christopher W, Smith Amber L, Wu Huiyun, Wang Yong-Dong, Valentine Marc, Neale Geoffrey, Vogel Peter, Pounds Stanley, Schuetz John D, Ni Min, Kundu Mondira
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Sci Adv. 2025 Jan 3;11(1):eads8489. doi: 10.1126/sciadv.ads8489. Epub 2025 Jan 1.
The role of somatic mitochondrial DNA (mtDNA) mutations in leukemogenesis remains poorly characterized. To determine the impact of somatic mtDNA mutations on this process, we assessed the leukemogenic potential of hematopoietic progenitor cells (HPCs) from mtDNA mutator mice (Polg D257A) with or without NMyc overexpression. We observed a higher incidence of spontaneous leukemogenesis in recipients transplanted with heterozygous Polg HPCs and a lower incidence of NMyc-driven leukemia in those with homozygous Polg HPCs compared to controls. Although mtDNA mutations in heterozygous and homozygous HPCs caused similar baseline impairments in mitochondrial function, only heterozygous HPCs responded to and supported altered metabolic demands associated with NMyc overexpression. Homozygous HPCs showed altered glucose utilization with pyruvate dehydrogenase inhibition due to increased phosphorylation, exacerbated by NMyc overexpression. The impaired growth of NMyc-expressing homozygous HPCs was partially rescued by inhibiting pyruvate dehydrogenase kinase, highlighting a relationship between mtDNA mutation burden and metabolic plasticity in leukemogenesis.
体细胞线粒体DNA（mtDNA）突变在白血病发生中的作用仍未得到充分表征。为了确定体细胞mtDNA突变对这一过程的影响，我们评估了来自mtDNA突变小鼠（Polg D257A）的造血祖细胞（HPC）在有或无NMyc过表达情况下的白血病发生潜能。我们观察到，与对照组相比，接受杂合Polg HPC移植的受体自发白血病发生率更高，而接受纯合Polg HPC移植的受体中NMyc驱动的白血病发生率更低。尽管杂合和纯合HPC中的mtDNA突变在线粒体功能方面引起了类似的基线损伤，但只有杂合HPC对与NMyc过表达相关的代谢需求改变有反应并提供支持。纯合HPC由于磷酸化增加而表现出丙酮酸脱氢酶抑制导致的葡萄糖利用改变，NMyc过表达使其加剧。通过抑制丙酮酸脱氢酶激酶，表达NMyc的纯合HPC受损的生长得到部分挽救，这突出了白血病发生中mtDNA突变负担与代谢可塑性之间的关系。
