Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo.
Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo.
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DOI：
10.1084/jem.20131141
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发表时间：
2013-11-18
期刊：
影响因子：
--
通讯作者：
Levine RL
中科院分区：
文献类型：
--
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
ASXL1的缺失会导致骨髓增生异常综合征，而伴随的TET2的缺失会恢复HSC的自我更新，并引发不同于单基因敲除小鼠的更严重的疾病表型。体细胞性梳状样突变(ASXL1)突变发生在10%-30%的髓系恶性肿瘤患者中，最常见的是骨髓增生异常综合征(MDS)，并与不良结局有关。生殖系ASXL1突变发生在Bohring-Opitz综合征患者中。在这里，我们发现ASXL1的结构性缺失会导致发育异常，包括眼球缺失、小头畸形、腭裂和下颌畸形。相反，在造血干细胞/祖细胞数量增加的情况下，ASXL1的造血特异性缺失会导致进行性、多系细胞减少和异型增生，这是人类MDS的特征。与ASXL1基因敲除(KO)小鼠相比，连续移植ASXL1基因缺失的造血细胞导致致死性髓系疾病的潜伏期更短。ASXL1缺失减少了造血干细胞的自我更新，这可以通过同时缺失TET2来恢复，TET2是MDS患者中常见的与ASXL1共突变的基因。此外，复合ASXL1/TET2缺失导致MDS表型，与单基因KO小鼠相比死亡更快。ASXL1缺失导致H3K27三甲基化的全球减少和已知的造血调节因子的表达失调。对造血细胞中ASXL1的RNA-Seq/ChIP-Seq分析确定了差异表达基因的一个子集作为ASXL1的直接靶点。这些发现强调了ASXL1在Polycomb组的功能、发育和造血中的重要性。
Loss of Asxl1 results in myelodysplastic syndrome, whereas concomitant deletion of Tet2 restores HSC self-renewal and triggers a more severe disease phenotype distinct from that seen in single-gene knockout mice. Somatic Addition of Sex Combs Like 1 (ASXL1) mutations occur in 10–30% of patients with myeloid malignancies, most commonly in myelodysplastic syndromes (MDSs), and are associated with adverse outcome. Germline ASXL1 mutations occur in patients with Bohring-Opitz syndrome. Here, we show that constitutive loss of Asxl1 results in developmental abnormalities, including anophthalmia, microcephaly, cleft palates, and mandibular malformations. In contrast, hematopoietic-specific deletion of Asxl1 results in progressive, multilineage cytopenias and dysplasia in the context of increased numbers of hematopoietic stem/progenitor cells, characteristic features of human MDS. Serial transplantation of Asxl1-null hematopoietic cells results in a lethal myeloid disorder at a shorter latency than primary Asxl1 knockout (KO) mice. Asxl1 deletion reduces hematopoietic stem cell self-renewal, which is restored by concomitant deletion of Tet2, a gene commonly co-mutated with ASXL1 in MDS patients. Moreover, compound Asxl1/Tet2 deletion results in an MDS phenotype with hastened death compared with single-gene KO mice. Asxl1 loss results in a global reduction of H3K27 trimethylation and dysregulated expression of known regulators of hematopoiesis. RNA-Seq/ChIP-Seq analyses of Asxl1 in hematopoietic cells identify a subset of differentially expressed genes as direct targets of Asxl1. These findings underscore the importance of Asxl1 in Polycomb group function, development, and hematopoiesis.
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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：
3.7
作者：
Haferlach, Claudia;Bacher, Ulrike;Haferlach, Torsten
通讯作者：
Haferlach, Torsten
影响因子：
20.3
作者：
Fisher, Cynthia L.;Pineault, Nicolas;Brock, Hugh W.
通讯作者：
Brock, Hugh W.
影响因子：
50.3
作者：
Moran-Crusio K;Reavie L;Shih A;Abdel-Wahab O;Ndiaye-Lobry D;Lobry C;Figueroa ME;Vasanthakumar A;Patel J;Zhao X;Perna F;Pandey S;Madzo J;Song C;Dai Q;He C;Ibrahim S;Beran M;Zavadil J;Nimer SD;Melnick A;Godley LA;Aifantis I;Levine RL
通讯作者：
Levine RL
DOI：
10.1056/nejmoa1013343
发表时间：
2011-06-30
期刊：
The New England journal of medicine
影响因子：
--
作者：
Bejar R;Stevenson K;Abdel-Wahab O;Galili N;Nilsson B;Garcia-Manero G;Kantarjian H;Raza A;Levine RL;Neuberg D;Ebert BL
通讯作者：
Ebert BL