身体mtDNA突变负担在白血病发生过程中塑造了代谢可塑性
Xiujie Li-Harms1, Jingjun Lu1, Yu Fukuda2
1Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Science advances
|January 1, 2025
概括
身体线粒体DNA (mtDNA) 突变影响白血病的发展. 虽然异构突变促进了自发白血病,但同构突变通过改变细胞代谢和生长来阻碍NMyc驱动的白血病.
科学领域:
- 线粒体遗传学线粒体遗传学
- 癌症生物学 癌症生物学
- 血液形成 血液形成 血液形成
背景情况:
- 肉体线粒体DNA (mtDNA) 突变在白血病发生过程中的作用尚不清楚.
- 线粒体功能障碍越来越被认为是癌症发展的一个因素.
研究的目的:
- 调查体质mtDNA突变对造血细胞原生细胞 (HPC) 致白血病潜力的影响.
- 评估mtDNA突变与白血病中的NMyc瘤基因之间的相互作用.
主要方法:
- 使用mtDNA突变小鼠 (Polg D257A) 具有不同程度的mtDNA突变负担 (异合体和同合体).
- 将移植的造血原生细胞 (HPC) 移植到接受者小鼠中,有或没有NMyc过度表达.
- 分析了白血病发生率,线粒体功能和细胞代谢 (葡萄糖利用,酸盐脱酶活性).
主要成果:
- 异性Polg HPCs显示自发白血病发生增加;同性Polg HPCs显示减少了NMyc驱动的白血病.
- 异合体和同合体mtDNA突变都影响了基线线粒体功能,但只有异合体HPC支持了NMyc驱动的代谢需求.
- 同胞性HPCs显示出改变的葡萄糖代谢和酸盐脱酶抑制,NMyc加剧了这种情况,通过抑制酸盐脱酶激酶来部分挽救.
结论:
- 身体mtDNA突变显著影响白血病发生,其影响因突变负担和瘤基因合作而异.
- 代谢可塑性,特别是葡萄糖利用率和酸盐脱酶活性,是NMyc驱动型白血病中mtDNA突变负载调节的关键因素.
- 这些发现突出了线粒体完整性,代谢适应和癌症发展之间的复杂关系.
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