SIRT2 regulates proliferation and chemotherapy response of MLL-ENL-driven acute myeloid leukemia.
SIRT2 regulates proliferation and chemotherapy response of MLL-ENL-driven acute myeloid leukemia.
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SIRT2 调节 MLL-ENL 驱动的急性髓系白血病的增殖和化疗反应。
DOI：
10.1016/j.bbrc.2022.01.081
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发表时间：
2022-03-12
影响因子：
3.1
通讯作者：
Li, Bing
中科院分区：
文献类型：
--
作者：
Hao, Caiqing;Shao, Xianyu;Song, Juan;Peng, Mengyuan;Lao, Yimin;Mack, Ryan;Zhang, Lei;Wei, Wei;Liu, Na;Wang, Tian;Wu, Yuanyuan;Feng, Lanyao;Yin, Lijun;Wang, Shouxin;Sun, Xiaojian;Chen, Saijuan;Zhang, Jiwang;Li, Bing
MLL-AF9 和 MLL-ENL 白血病融合蛋白均通过其 N 端 DNA/组蛋白结合混合谱系白血病 1 结构域及其 AF9 或 ENL 的 C 端片段（包含非结构化接头区域和 ANC1 同源结构域（可招募转录因子））驱动造血细胞的致癌转化。尽管结构相似，但携带 MLL-ENL 的急性髓系白血病 (AML) 患者比携带 MLL-AF9 的患者表现出更多不良后果。我们使用小鼠模型概括了这两种 MLL 融合驱动的 AML 的临床模式，发现 MLL-ENL AML 细胞比 MLL-AF9 细胞表现出更慢的细胞周期进展和对标准化疗的更多抵抗力。这些表型主要由 ENL 的接头区域和其中高度保守的赖氨酸残基 K469 控制。用乙酰化模拟谷氨酰胺取代 K469 消除了 MLL-ENL 抑制增殖和促进化疗耐药的能力。我们发现脱乙酰酶 Sirt2 可能作为 MLL-ENL 的上游调节因子。 Sirt2 的缺失促进了具有 MLL 融合的 AML 细胞的增殖。重要的是，Sirt2 的缺失大大增强了 MLL-ENL AML 细胞对化疗的敏感性。总而言之，我们的研究发现了 Sirt2 在白血病发生中的独特调节作用，并建议将 SIRT2 作为一种提高 MLL-ENL AML 对化疗耐受性的新方法。
Both MLL-AF9 and MLL-ENL leukemia fusion proteins drive oncogenic transformation of hematopoietic cells through their N-terminal DNA/histone binding mixed-lineage leukemia 1 domain and their C-terminal fragment of AF9 or ENL containing a unstructured linker region and the ANC1 homology domain, which recruits transcription factors. Despite of their structural similarity, acute myeloid leukemia (AML) patients bearing MLL-ENL show more adverse outcomes compared to those with MLL-AF9. We recapitulated the clinical patterns of these two MLL-fusions driven AMLs using murine models and found that MLL-ENL AML cells showed slower cell cycle progression and more resistance to standard chemotherapy than MLL-AF9 cells. These phenotypes were primarily controlled by the linker regions of ENL and a highly conserved lysine residue K469 within. Substitution of K469 with an acetylated mimic glutamine abolished the ability of MLL-ENL to suppress proliferation and promote chemo-resistance. We showed that deacetylase Sirt2 might act as an upstream regulator of MLL-ENL. Deletion of Sirt2 promoted proliferation of AML cells with either MLL fusions. Importantly, loss of Sirt2 greatly enhanced the sensitivity of the MLL-ENL AML cells to chemo-treatment. Taken together, our study uncovered a unique regulatory role of Sirt2 in leukemogenesis and suggested targeting SIRT2 as a new way to sensitize MLL-ENL AML patience for chemotherapy.
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影响因子：
5.2
作者：
Grigsby SM;Friedman A;Chase J;Waas B;Ropa J;Serio J;Shen C;Muntean AG;Maillard I;Nikolovska-Coleska Z
通讯作者：
Nikolovska-Coleska Z
影响因子：
64.8
作者：
Erb MA;Scott TG;Li BE;Xie H;Paulk J;Seo HS;Souza A;Roberts JM;Dastjerdi S;Buckley DL;Sanjana NE;Shalem O;Nabet B;Zeid R;Offei-Addo NK;Dhe-Paganon S;Zhang F;Orkin SH;Winter GE;Bradner JE
通讯作者：
Bradner JE
影响因子：
2.9
作者：
Schulze, Julia M.;Wang, Alice Y.;Kobor, Michael S.
通讯作者：
Kobor, Michael S.
影响因子：
4.3
作者：
Inoue, Toshiaki;Hiratsuka, Masaharu;Oshimura, Mitsuo
通讯作者：
Oshimura, Mitsuo
乙酰化模拟物中的单个核小体改变了压实核小体阵列中局部DNA的可及性。
影响因子：
4.6
作者：
Mishra LN;Pepenella S;Rogge R;Hansen JC;Hayes JJ
通讯作者：
Hayes JJ