PRPF8 defects cause missplicing in myeloid malignancies.
PRPF8 defects cause missplicing in myeloid malignancies.
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作者：
剪接体成分的突变在髓系肿瘤中很常见。受影响的基因之一，PRPF8，编码进化上最保守的剪接体蛋白。我们分别在15/447例和24/450例患者中发现了复发的体细胞PRPF8突变或半合子缺失。50%的PRPF8突变和del(17p)病例发生在AML中，预后较差。在无SF3B1突变的病例中，PRPF8缺陷与成髓细胞和环状铁母细胞的增加有关。K562和CD34+原代骨髓细胞中PRPF8基因敲除后，细胞增殖能力增强。对PRPF8异常患者的原代细胞进行全RNA深度测序，显示出一致的错接缺陷。在酵母模型中，引入Prp8的同源突变消除了在RNA剪接过程的第二步实验中产生的一个区块，这表明突变体在校对功能方面存在缺陷。总之，对临床和功能结果的探索表明，PRPF8是髓系肿瘤中的一个新的白血病致病基因，其独特的表型可能是通过异常剪接表现出来的。
Mutations of spliceosome components are common in myeloid neoplasms. One of the affected genes, PRPF8, encodes the most evolutionarily conserved spliceosomal protein. We identified either recurrent somatic PRPF8 mutations or hemizygous deletions in 15/447 and 24/450 cases, respectively. 50% of PRPF8 mutant and del(17p) cases were found in AML and conveyed poor prognosis. PRPF8 defects correlated with increased myeloblasts and ring sideroblasts in cases without SF3B1 mutations. Knockdown of PRPF8 in K562 and CD34+ primary bone marrow cells increased proliferative capacity. Whole RNA deep sequencing of primary cells from patients with PRPF8 abnormalities demonstrated consistent missplicing defects. In yeast models, homologous mutations introduced into Prp8 abrogated a block experimentally produced in the second step of the RNA splicing process suggesting that the mutants have defects in proof-reading functions. In sum, the exploration of clinical and functional consequences suggests that PRPF8 is a novel leukemogenic gene in myeloid neoplasms with a distinct phenotype likely manifested through aberrant splicing.
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影响因子：
11.4
作者：
通讯作者：
--
影响因子：
8
作者：
Allende-Vega, N.;Dayal, S.;Saville, M. K.
通讯作者：
Saville, M. K.
影响因子：
3.5
作者：
Badhai, Jitendra;Frojmark, Anne-Sophie;Dahl, Niklas
通讯作者：
Dahl, Niklas
DOI：
10.1056/nejmoa1005143
发表时间：
2010-12-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ley TJ;Ding L;Walter MJ;McLellan MD;Lamprecht T;Larson DE;Kandoth C;Payton JE;Baty J;Welch J;Harris CC;Lichti CF;Townsend RR;Fulton RS;Dooling DJ;Koboldt DC;Schmidt H;Zhang Q;Osborne JR;Lin L;O'Laughlin M;McMichael JF;Delehaunty KD;McGrath SD;Fulton LA;Magrini VJ;Vickery TL;Hundal J;Cook LL;Conyers JJ;Swift GW;Reed JP;Alldredge PA;Wylie T;Walker J;Kalicki J;Watson MA;Heath S;Shannon WD;Varghese N;Nagarajan R;Westervelt P;Tomasson MH;Link DC;Graubert TA;DiPersio JF;Mardis ER;Wilson RK
通讯作者：
Wilson RK
影响因子：
6.5
作者：
Maciejewski JP;Padgett RA
通讯作者：
Padgett RA