Loss-of-function TET2 mutations (TET2^MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2^MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2^MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2^MT myeloid neoplasia (MN), clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2^MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2^MT leukemia.

TET2 功能丧失突变 ( TET2 ^MT ) 在骨髓瘤中很常见。TET2 是一种 DNA 双加氧酶，需要 2-酮戊二酸和 Fe(II) 来氧化 5-甲基胞嘧啶。TET2 ^MT因此导致高甲基化和转录抑制。抗坏血酸 (AA) 通过促进 Fe(III)/Fe(II) 氧化还原反应来增加双加氧酶活性，并可以通过恢复双加氧酶活性来减轻TET2 ^MT的一些生物学后果。在此，我们报告 AA 在预防TET2 ^MT中的效用骨髓瘤 (MN)，阐明了 TET2-AA 相互作用的机制基础，并证明 AA 恢复细胞中 TET2 活性的能力取决于 N 端和 C 端赖氨酸乙酰化以及 TET2 MT的^性质。因此，乙酰转移酶和组蛋白脱乙酰酶的药理调节可能会调节 TET 双加氧酶依赖性 AA 效应。因此，我们的研究强调了可能增强或减弱 AA 对 TET2 影响的因素的贡献，并为新的治疗方法（包括 AA 与 I/II 类 HDAC 抑制剂或 Sirtuin 激活剂联合治疗 TET2 MT 白血病）提供了理论^基础。