Deregulation of tumor suppressive ASXL1-PTEN/AKT axis in myeloid malignancies.
Deregulation of tumor suppressive ASXL1-PTEN/AKT axis in myeloid malignancies.
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骨髓恶性肿瘤中肿瘤抑制 ASXL1-PTEN/AKT 轴的失调
DOI：
10.1093/jmcb/mjaa011
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发表时间：
2020-09-01
影响因子：
5.5
通讯作者：
Wu X
中科院分区：
文献类型：
--
作者：
Cao L;Xia X;Kong Y;Jia F;Yuan B;Li R;Li Q;Wang Y;Cui M;Dai Z;Zheng H;Christensen J;Zhou Y;Wu X
表观遗传调节因子的突变在人类肿瘤中普遍存在。ASXL 1在骨髓恶性肿瘤中经常发生突变。我们先前发现ASXL 1与BAP 1一起形成复合物，该复合物可以使组蛋白H2 A（H2 AK 119 ub 1）（Polycomb抑制标记）上的单泛素化赖氨酸119去泛素化。然而，一个完整的机制理解ASXL 1在转录调控和肿瘤抑制仍有待确定。在这里，我们发现，Asxl 1的耗竭赋予小鼠32 D细胞IL 3非依赖性生长至少部分是由于持续激活PI 3 K/AKT信号。因此，Asxl 1对Pten的转录激活至关重要，Pten是AKT活性的关键负调节因子。然后，我们证实，Asxl 1是专门富集和所需的H2 AK 119去泛素化在Pten启动子。有趣的是，ASXL 1和PTEN表达水平在人血细胞中呈正相关，并且ASXL 1突变与人骨髓恶性肿瘤中PTEN的较低表达水平相关。此外，具有ASXL 1下调或突变的恶性细胞对AKT抑制剂MK 2206表现出更高的敏感性。总的来说，这项研究将PTEN/AKT信号传导轴与骨髓恶性肿瘤中失调的表观遗传变化联系起来。它还为ASXL 1突变患者提供了基于机制的治疗原理。
Mutations of epigenetic regulators are pervasive in human tumors. ASXL1 is frequently mutated in myeloid malignancies. We previously found that ASXL1 forms together with BAP1 a complex that can deubiquitinylate mono-ubiquitinylated lysine 119 on histone H2A (H2AK119ub1), a Polycomb repressive mark. However, a complete mechanistic understanding of ASXL1 in transcriptional regulation and tumor suppression remains to be defined. Here, we find that depletion of Asxl1 confers murine 32D cells to IL3-independent growth at least partly due to sustained activation of PI3K/AKT signaling. Consistently, Asxl1 is critical for the transcriptional activation of Pten, a key negative regulator of AKT activity. Then we confirm that Asxl1 is specifically enriched and required for H2AK119 deubiquitylation at the Pten promoter. Interestingly, ASXL1 and PTEN expression levels are positively correlated in human blood cells and ASXL1 mutations are associated with lower expression levels of PTEN in human myeloid malignancies. Furthermore, malignant cells with ASXL1 downregulation or mutations exhibit higher sensitivity to the AKT inhibitor MK2206. Collectively, this study has linked the PTEN/AKT signaling axis to deregulated epigenetic changes in myeloid malignancies. It also provides a rationale for mechanism-based therapy for patients with ASXL1 mutations.
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影响因子：
28.5
作者：
Gelsi-Boyer V;Brecqueville M;Devillier R;Murati A;Mozziconacci MJ;Birnbaum D
通讯作者：
Birnbaum D
影响因子：
12.3
作者：
Kandasamy K;Mohan SS;Raju R;Keerthikumar S;Kumar GS;Venugopal AK;Telikicherla D;Navarro JD;Mathivanan S;Pecquet C;Gollapudi SK;Tattikota SG;Mohan S;Padhukasahasram H;Subbannayya Y;Goel R;Jacob HK;Zhong J;Sekhar R;Nanjappa V;Balakrishnan L;Subbaiah R;Ramachandra YL;Rahiman BA;Prasad TS;Lin JX;Houtman JC;Desiderio S;Renauld JC;Constantinescu SN;Ohara O;Hirano T;Kubo M;Singh S;Khatri P;Draghici S;Bader GD;Sander C;Leonard WJ;Pandey A
通讯作者：
Pandey A
影响因子：
50.3
作者：
Abdel-Wahab O;Adli M;LaFave LM;Gao J;Hricik T;Shih AH;Pandey S;Patel JP;Chung YR;Koche R;Perna F;Zhao X;Taylor JE;Park CY;Carroll M;Melnick A;Nimer SD;Jaffe JD;Aifantis I;Bernstein BE;Levine RL
通讯作者：
Levine RL
影响因子：
20.3
作者：
Gutierrez, Alejandro;Sanda, Takaomi;Look, A. Thomas
通讯作者：
Look, A. Thomas
DOI：
10.1084/jem.20131141
发表时间：
2013-11-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Abdel-Wahab O;Gao J;Adli M;Dey A;Trimarchi T;Chung YR;Kuscu C;Hricik T;Ndiaye-Lobry D;Lafave LM;Koche R;Shih AH;Guryanova OA;Kim E;Li S;Pandey S;Shin JY;Telis L;Liu J;Bhatt PK;Monette S;Zhao X;Mason CE;Park CY;Bernstein BE;Aifantis I;Levine RL
通讯作者：
Levine RL