The occurrence of autophagy dysregulation is vital in the development of myelodysplastic syndrome and its transformation to acute myeloid leukemia. However, the mechanisms are largely unknown. Here, we have investigated the mechanism of the bcl6 corepressor mutation in myelodysplastic syndrome development and its transformation to acute myeloid leukemia. We identified a novel pathway involving histone deacetylase 6 and forkhead box protein O1, which leads to autophagy defects following the bcl6 corepressor mutation. And this further causes apoptosis and cell cycle arrest. The bcl6 corepressor-mutation-repressed autophagy resulted in the accumulation of damaged mitochondria, DNA, and reactive oxygen species in myelodysplastic syndrome cells, which could then lead to genomic instability and spontaneous mutation. Our results suggest that the bcl6 corepressor inactivating mutations exert pro-carcinogenic effects through survival strike, which is only an intermediate process. These findings provide mechanistic insights into the role of the bcl6 corepressor gene in myelodysplastic syndrome.

自噬失调的发生对于骨髓增生异常综合征的发展及其向急性髓系白血病的转化至关重要。然而，其机制很大程度上是未知的。在此，我们研究了 bcl6 辅阻遏物突变在骨髓增生异常综合征发展及其转化为急性髓系白血病中的机制。我们发现了一条涉及组蛋白脱乙酰酶 6 和叉头盒蛋白 O1 的新途径，该途径会导致 bcl6 辅阻遏物突变后的自噬缺陷。这进一步导致细胞凋亡和细胞周期停滞。bcl6 辅阻遏物突变抑制自噬导致骨髓增生异常综合征细胞中受损的线粒体、DNA 和活性氧积累，从而导致基因组不稳定和自发突变。我们的结果表明，bcl6 辅阻遏物失活突变通过生存罢工发挥促癌作用，这只是一个中间过程。这些发现为 bcl6 辅阻遏基因在骨髓增生异常综合征中的作用提供了机制见解。