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Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia.
Communications Biology ( IF 5.2 ) Pub Date : 2020-09-07 , DOI: 10.1038/s42003-020-01220-9
Yihong Guan 1 , Edward F Greenberg 1, 2 , Metis Hasipek 1 , Shi Chen 3, 4 , Xiaochen Liu 3 , Cassandra M Kerr 1 , Daniel Gackowski 5 , Ewelina Zarakowska 5 , Tomas Radivoyevitch 1 , Xiaorong Gu 1 , Belinda Willard 6 , Valeria Visconte 1 , Hideki Makishima 1, 7 , Aziz Nazha 1, 2 , Mridul Mukherji 8 , Mikkael A Sekeres 2 , Yogen Saunthararajah 1 , Ryszard Oliński 5 , Mingjiang Xu 3, 4 , Jaroslaw P Maciejewski 1, 2 , Babal K Jha 1
Affiliation  

Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT 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 TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT 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 TET2MT. 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 TET2MT leukemia.



中文翻译:

抗坏血酸治疗 TET2 突变型骨髓瘤的背景依赖性效应。

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

更新日期:2020-09-08
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