Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene U2af1.
Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene U2af1.
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DOI：
10.1073/pnas.1812669115
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发表时间：
2018-10-30
影响因子：
11.1
通讯作者：
Varmus H
中科院分区：
文献类型：
--
作者：
Fei DL;Zhen T;Durham B;Ferrarone J;Zhang T;Garrett L;Yoshimi A;Abdel-Wahab O;Bradley RK;Liu P;Varmus H
在骨髓增生异常综合征（MDS）和MDS相关的急性髓性白血病（AML）中经常发现一些剪接因子基因的体细胞突变，这些血癌几乎没有有效的治疗选择。然而，这些突变的病理生理学影响仍然很差的特点。在这里，我们报告的小鼠模型的建立，研究一个常见的剪接因子突变，U2 AF 1（S34 F）。在鼠造血区室中产生突变蛋白以类似于人MDS的方式破坏造血。我们进一步确定Runx 1基因的缺失和其他已知的致癌突变可能与U2 af 1（S34 F）合作，在小鼠中引起坦率的AML。然而，U2 af 1（S34 F）突变在三个AML病例中的两个中不存在，这增加了这种突变蛋白在肿瘤维持中起重要作用的可能性。影响剪接体蛋白U2 AF 1的突变通常见于骨髓增生异常综合征（MDS）和继发性急性髓系白血病（sAML）。我们已经产生了携带Cre依赖性敲入等位基因U2 af 1（S34 F）的小鼠，这是人类癌症中遇到的最常见的U2 AF 1突变等位基因的鼠版本。Cre介导的重组在小鼠造血谱系中引起RNA剪接的变化，以及多谱系血细胞减少、大红细胞性贫血、造血干细胞和祖细胞减少、低度发育不良和可移植性受损，但没有寿命缩短或白血病发展。在试图确定U2 af 1（S34 F）的协同变化，促进白血病的发生，我们结合U2 af 1（S34 F）与Runx 1缺陷的小鼠，并进一步处理小鼠的诱变剂，N-乙基-N-亚硝基脲（ENU）。总体而言，16只ENU处理的化合物转基因小鼠中有3只发生AML。然而，AML没有出现在其他基因型或没有ENU治疗的小鼠中。对三种AML的DNA进行测序，发现与人类AML驱动因子同源的体细胞突变，包括Tet 2、Gata 2、Idh 1和Ikzf 1中预测的功能丧失或获得突变。然而，在三个AML病例中的两个中，工程化U2 af 1（S34 F）错义突变恢复为WT，这意味着一旦白血病建立，U2 af 1（S34 F）就被抑制，甚至被选择。
Somatic mutations in some splicing factor genes are frequently found in myelodysplastic syndromes (MDS) and MDS-related acute myeloid leukemia (AML), blood cancers with few effective treatment options. However, the pathophysiological effects of these mutations remain poorly characterized. Here, we report the establishment of mouse models to study a common splicing factor mutation, U2AF1(S34F). Production of the mutant protein in the murine hematopoietic compartment disrupts hematopoiesis in ways resembling human MDS. We further identified deletion of the Runx1 gene and other known oncogenic mutations as changes that might collaborate with U2af1(S34F) to give rise to frank AML in mice. However, the U2af1(S34F) mutation was absent in two of the three AML cases, raising the possibility that this mutant protein plays a dispensable role in tumor maintenance. Mutations affecting the spliceosomal protein U2AF1 are commonly found in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). We have generated mice that carry Cre-dependent knock-in alleles of U2af1(S34F), the murine version of the most common mutant allele of U2AF1 encountered in human cancers. Cre-mediated recombination in murine hematopoietic lineages caused changes in RNA splicing, as well as multilineage cytopenia, macrocytic anemia, decreased hematopoietic stem and progenitor cells, low-grade dysplasias, and impaired transplantability, but without lifespan shortening or leukemia development. In an attempt to identify U2af1(S34F)-cooperating changes that promote leukemogenesis, we combined U2af1(S34F) with Runx1 deficiency in mice and further treated the mice with a mutagen, N-ethyl-N-nitrosourea (ENU). Overall, 3 of 16 ENU-treated compound transgenic mice developed AML. However, AML did not arise in mice with other genotypes or without ENU treatment. Sequencing DNA from the three AMLs revealed somatic mutations homologous to those considered to be drivers of human AML, including predicted loss- or gain-of-function mutations in Tet2, Gata2, Idh1, and Ikzf1. However, the engineered U2af1(S34F) missense mutation reverted to WT in two of the three AML cases, implying that U2af1(S34F) is dispensable, or even selected against, once leukemia is established.
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DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
在健康个体中预测急性髓样白血病的风险。
影响因子：
64.8
作者：
Abelson S;Collord G;Ng SWK;Weissbrod O;Mendelson Cohen N;Niemeyer E;Barda N;Zuzarte PC;Heisler L;Sundaravadanam Y;Luben R;Hayat S;Wang TT;Zhao Z;Cirlan I;Pugh TJ;Soave D;Ng K;Latimer C;Hardy C;Raine K;Jones D;Hoult D;Britten A;McPherson JD;Johansson M;Mbabaali F;Eagles J;Miller JK;Pasternack D;Timms L;Krzyzanowski P;Awadalla P;Costa R;Segal E;Bratman SV;Beer P;Behjati S;Martincorena I;Wang JCY;Bowles KM;Quirós JR;Karakatsani A;La Vecchia C;Trichopoulou A;Salamanca-Fernández E;Huerta JM;Barricarte A;Travis RC;Tumino R;Masala G;Boeing H;Panico S;Kaaks R;Krämer A;Sieri S;Riboli E;Vineis P;Foll M;McKay J;Polidoro S;Sala N;Khaw KT;Vermeulen R;Campbell PJ;Papaemmanuil E;Minden MD;Tanay A;Balicer RD;Wareham NJ;Gerstung M;Dick JE;Brennan P;Vassiliou GS;Shlush LI
通讯作者：
Shlush LI
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
56.9
作者：
Gu, Y;Filippi, MD;Williams, DA
通讯作者：
Williams, DA