The distinct biological implications of Asxl1 mutation and its roles in leukemogenesis revealed by a knock-in mouse model.
The distinct biological implications of Asxl1 mutation and its roles in leukemogenesis revealed by a knock-in mouse model.
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DOI：
10.1186/s13045-017-0508-x
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发表时间：
2017-07-11
影响因子：
28.5
通讯作者：
Tien HF
中科院分区：
文献类型：
--
作者：
Hsu YC;Chiu YC;Lin CC;Kuo YY;Hou HA;Tzeng YS;Kao CJ;Chuang PH;Tseng MH;Hsiao TH;Chou WC;Tien HF
额外的性梳样1（ASXL 1）经常在骨髓恶性肿瘤中突变。最近的研究表明，造血特异性缺失的ASXL 1或突变ASXL 1的过表达导致小鼠骨髓增生异常样疾病。然而，“生理”剂量的突变体ASXL 1的实际效果仍然未被探索。我们建立了一个基因敲入的小鼠模型，携带最常见的Asxl 1突变，并研究其对小鼠造血系统的病理生理影响。杂合子（Asxl 1 tm/+）骨髓细胞具有较高的体外增殖能力，如鹅卵石区形成试验和系列重新铺板试验中的更多集落所示。另一方面，在移植试验期间，来自Asxl 1 tm/+小鼠的供体造血细胞在受体中下降得更快，表明长期体内再增殖能力受损。在突变小鼠的整个生命周期中，没有明显的血液疾病，表明单独的Asxl 1突变不足以导致白血病的发生。然而，这种突变促进了过表达MN 1的骨髓细胞的植入。对ASXL 1突变与野生型人白血病细胞以及杂合子与野生型小鼠骨髓前体细胞（有或无MN 1过表达）的总体基因表达谱的分析，突出了体内Asxl 1突变与缺氧、多能祖细胞、造血干细胞、KRAS和MEK基因集表达的相关性。ChIP-Seq分析揭示了造血前体中Asxl 1突变调节的H3 K27三甲基化的全球模式。我们提出了第一个Asxl 1突变敲入小鼠模型，并显示突变的Asxl 1降低MN 1驱动的植入阈值，并对生理和恶性造血表现出不同的生物学功能，尽管它不足以导致血液恶性肿瘤。本文的在线版本（doi：10.1186/s13045-017-0508-x）包含补充材料，可供授权用户使用。
Additional sex combs-like 1 (ASXL1) is frequently mutated in myeloid malignancies. Recent studies showed that hematopoietic-specific deletion of Asxl1 or overexpression of mutant ASXL1 resulted in myelodysplasia-like disease in mice. However, actual effects of a “physiological” dose of mutant ASXL1 remain unexplored. We established a knock-in mouse model bearing the most frequent Asxl1 mutation and studied its pathophysiological effects on mouse hematopoietic system. Heterozygotes (Asxl1 tm/+) marrow cells had higher in vitro proliferation capacities as shown by more colonies in cobblestone-area forming assays and by serial re-plating assays. On the other hand, donor hematopoietic cells from Asxl1 tm/+ mice declined faster in recipients during transplantation assays, suggesting compromised long-term in vivo repopulation abilities. There were no obvious blood diseases in mutant mice throughout their life-span, indicating Asxl1 mutation alone was not sufficient for leukemogenesis. However, this mutation facilitated engraftment of bone marrow cell overexpressing MN1. Analyses of global gene expression profiles of ASXL1-mutated versus wild-type human leukemia cells as well as heterozygote versus wild-type mouse marrow precursor cells, with or without MN1 overexpression, highlighted the association of in vivo Asxl1 mutation to the expression of hypoxia, multipotent progenitors, hematopoietic stem cells, KRAS, and MEK gene sets. ChIP-Seq analysis revealed global patterns of Asxl1 mutation-modulated H3K27 tri-methylation in hematopoietic precursors. We proposed the first Asxl1 mutation knock-in mouse model and showed mutated Asxl1 lowered the threshold of MN1-driven engraftment and exhibited distinct biological functions on physiological and malignant hematopoiesis, although it was insufficient to lead to blood malignancies. The online version of this article (doi:10.1186/s13045-017-0508-x) contains supplementary material, which is available to authorized users.
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影响因子：
11.2
作者：
Abdel-Wahab O;Manshouri T;Patel J;Harris K;Yao J;Hedvat C;Heguy A;Bueso-Ramos C;Kantarjian H;Levine RL;Verstovsek S
通讯作者：
Verstovsek S
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：
20.3
作者：
Beekman, Renee;Valkhof, Marijke G.;Touw, Ivo P.
通讯作者：
Touw, Ivo P.
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS
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