Defects in spliceosomal machinery: a new pathway of leukaemogenesis.
Defects in spliceosomal machinery: a new pathway of leukaemogenesis.
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DOI：
10.1111/j.1365-2141.2012.09158.x
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发表时间：
2012-07
影响因子：
6.5
通讯作者：
Padgett RA
中科院分区：
文献类型：
--
作者：
Maciejewski JP;Padgett RA
前体mRNA的正确剪接是蛋白质合成所必需的，因此是基本的细胞功能。在血液系统恶性肿瘤，包括骨髓肿瘤和慢性淋巴细胞白血病中发现了多种体细胞剪接体突变，指出了一种新的白血病发生途径，涉及剪接体功能障碍。理论上，剪接体突变可导致不正确剪接位点的激活、内含子保留或异常选择性剪接，其发生在由单个剪接体蛋白突变产生的模式中。此类事件可在蛋白质同种型之间产生有缺陷的平衡，导致功能后果，包括增殖和分化的有缺陷的调节。观察到的高度特异性错义突变的发生模式加上无义突变和缺失的缺乏，意味着功能获得或更好的功能障碍获得机制。下游基因如肿瘤抑制基因的不正确剪接可通过无义介导的mRNA降解导致单倍表达不足。因此，取决于受影响蛋白质的模式，切片体突变可能导致对肿瘤抑制基因的类似功能效应，如染色体缺失、表观遗传沉默或失活/亚型突变。目前正在研究最常见突变的预后价值及其在临床环境中的表型关联。剪接体突变可能表明对以合成致死方法形式应用的剪接体抑制剂的敏感性。本文讨论了血液系统恶性肿瘤中剪接体研究的最新进展。
Proper splicing of pre-mRNA is required for protein synthesis and therefore is a fundamental cellular function. The discovery of a variety of somatic spliceosomal mutations in hematologic malignancies, including myeloid neoplasms and chronic lymphocytic leukemia has pointed to a new leukemogenic pathway involving spliceosomal dysfunction. Theoretically, spliceosomal mutations can lead to activation of incorrect splice sites, intron retention or aberrant alternative splicing occurring in patterns generated by mutations of individual spliceosomal proteins. Such events can produce a defective balance between protein isoforms leading to functional consequences including defective regulation of proliferation and differentiation. The observed pattern of occurrence of highly specific missense mutations coupled with the lack of nonsense mutations and deletions, implies a gain-of-function or better gain-of-dysfunction mechanism. Incorrect splicing of downstream genes such as tumor suppressor genes may result in haploinsufficient expression through nonsense mediated mRNA decay. Thus sliceosomal mutations may, depending on the pattern of affected proteins, lead to similar functional effects on tumor suppressor genes as chromosomal deletions, epigenetic silencing or inactivating/hypomorphic mutations. The prognostic value of the most common mutations and their phenotypic association in the clinical setting is currently being investigated. It is likely that spliceosomal mutations may indicate sensitivity to spliceosome inhibitors applied in the form of a synthetic lethal approach. This manuscript discusses the most current aspects of spliceosomal research in the context of hematologic malignancies.
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影响因子：
10.5
作者：
Shen, Haihong;Zheng, Xuexiu;Green, Michael R.
通讯作者：
Green, Michael R.
影响因子：
64.5
作者：
Li, XL;Manley, JL
通讯作者：
Manley, JL
DOI：
10.1056/nejmoa1103283
发表时间：
2011-10-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
Papaemmanuil E;Cazzola M;Boultwood J;Malcovati L;Vyas P;Bowen D;Pellagatti A;Wainscoat JS;Hellstrom-Lindberg E;Gambacorti-Passerini C;Godfrey AL;Rapado I;Cvejic A;Rance R;McGee C;Ellis P;Mudie LJ;Stephens PJ;McLaren S;Massie CE;Tarpey PS;Varela I;Nik-Zainal S;Davies HR;Shlien A;Jones D;Raine K;Hinton J;Butler AP;Teague JW;Baxter EJ;Score J;Galli A;Della Porta MG;Travaglino E;Groves M;Tauro S;Munshi NC;Anderson KC;El-Naggar A;Fischer A;Mustonen V;Warren AJ;Cross NC;Green AR;Futreal PA;Stratton MR;Campbell PJ;Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium
通讯作者：
Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium
影响因子：
20.3
作者：
Malcovati L;Papaemmanuil E;Bowen DT;Boultwood J;Della Porta MG;Pascutto C;Travaglino E;Groves MJ;Godfrey AL;Ambaglio I;Gallì A;Da Vià MC;Conte S;Tauro S;Keenan N;Hyslop A;Hinton J;Mudie LJ;Wainscoat JS;Futreal PA;Stratton MR;Campbell PJ;Hellström-Lindberg E;Cazzola M;Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium and of the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative
通讯作者：
Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium and of the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative
影响因子：
5.7
作者：
Albert BJ;McPherson PA;O'Brien K;Czaicki NL;Destefino V;Osman S;Li M;Day BW;Grabowski PJ;Moore MJ;Vogt A;Koide K
通讯作者：
Koide K