Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network.
Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network.
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ASXL1 肿瘤衍生的新形态突变损害 BAP1-ASXL1-FOXK1/K2 转录网络
DOI：
10.1007/s13238-020-00754-2
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发表时间：
2021-07
期刊：
影响因子：
21.1
通讯作者：
Ye D
中科院分区：
文献类型：
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作者：
Xia YK;Zeng YR;Zhang ML;Liu P;Liu F;Zhang H;He CX;Sun YP;Zhang JY;Zhang C;Song L;Ding C;Tang YJ;Yang Z;Yang C;Wang P;Guan KL;Xiong Y;Ye D
额外的性梳样蛋白1（ASXL 1）与BRCA 1相关蛋白1（BAP 1）去泛素化酶相互作用，对抗多梳抑制复合物1（PRC 1）介导的组蛋白H2 A泛素化。BAP 1基因突变存在于多种人类恶性肿瘤中，而ASXL 1基因突变常发生于髓系肿瘤中，并与不良预后相关。几乎所有的ASXL 1突变都是杂合的移码突变或无义突变，位于中间或较小程度的C-末端区域，导致产生C-末端截短的突变ASXL 1蛋白。ASXL 1如何调节特定的靶基因以及ASXL 1的C端截短如何促进白血病发生尚不清楚。在这里，我们报告ASXL 1与叉头转录因子FOXK 1和FOXK 2相互作用，以调节FOXK 1/K2靶基因的子集。我们发现，在ASXL 1杂合子白血病细胞中，C端截短的突变ASXL 1蛋白的表达水平比野生型蛋白高得多，并且失去了与FOXK 1/K2相互作用的能力。突变等位基因的特异性缺失消除了C末端截短的ASXL 1的表达，并增加了野生型ASXL 1与BAP 1的结合，从而恢复了BAP 1-ASXL 1-FOXK 1/K2靶基因的表达，特别是那些参与葡萄糖代谢、氧传感和JAK-STAT 3信号传导途径的基因。除了FOXK 1/K2，我们还鉴定了其他DNA结合转录调节因子，包括与野生型ASXL 1相互作用的转录因子（TF），但不与C-末端截短突变体相互作用。我们的研究结果表明，ASXL 1突变导致新的等位基因，有助于白血病的发生，至少部分通过显性抑制野生型ASXL 1与BAP 1相互作用，从而削弱ASXL 1-BAP 1-TF在调节靶基因和白血病细胞生长的功能。
Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)-mediated histone H2A ubiquitylation. GermlineBAP1mutations are found in a spectrum of human malignancies, whileASXL1mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly allASXL1mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation ofASXL1promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein inASXL1heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes, particularly those involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling pathways. In addition to FOXK1/K2, we also identify other DNA-binding transcription regulators including transcription factors (TFs) which interact with wild-type ASXL1, but not C-terminally truncated mutant. Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.
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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：
20.3
作者：
Fisher, Cynthia L.;Pineault, Nicolas;Brock, Hugh W.
通讯作者：
Brock, Hugh W.
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
影响因子：
16.6
作者：
Asada S;Goyama S;Inoue D;Shikata S;Takeda R;Fukushima T;Yonezawa T;Fujino T;Hayashi Y;Kawabata KC;Fukuyama T;Tanaka Y;Yokoyama A;Yamazaki S;Kozuka-Hata H;Oyama M;Kojima S;Kawazu M;Mano H;Kitamura T
通讯作者：
Kitamura T
影响因子：
64.8
作者：
通讯作者：
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