Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia
Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia
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DOI：
10.1038/s42003-020-01220-9
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发表时间：
2020-09-07
影响因子：
5.9
通讯作者：
Jha, Babal K.
中科院分区：
文献类型：
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作者：
Guan, Yihong;Greenberg, Edward F.;Jha, Babal K.
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。在这里，我们报告了 AA 在预防 TET2(MT) 骨髓瘤 (MN) 中的效用，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，并为新的治疗方法提供了理论基础，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。通过使用 TET2 和抗坏血酸缺陷模型系统，Guan 等人表明，长期抗坏血酸治疗可延迟小鼠的骨髓瘤形成，并揭示赖氨酸残基翻译后修饰在肿瘤进化中调节 TET2 活性的复杂相互作用。
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. Using TET2- and ascorbic acid deficient model systems Guan et al show that long term treatment with ascorbic acid delays myeloid neoplasia in mice and reveal a complex interplay of post-translational modification of lysine residues that modulate TET2 activity in neoplastic evolution.