Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma.
Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma.
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DOI：
10.1038/ng.3473
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发表时间：
2016-02
期刊：
影响因子：
30.8
通讯作者：
Fitzgibbon J
中科院分区：
文献类型：
--
作者：
Okosun J;Wolfson RL;Wang J;Araf S;Wilkins L;Castellano BM;Escudero-Ibarz L;Al Seraihi AF;Richter J;Bernhart SH;Efeyan A;Iqbal S;Matthews J;Clear A;Guerra-Assunção JA;Bödör C;Quentmeier H;Mansbridge C;Johnson P;Davies A;Strefford JC;Packham G;Barrans S;Jack A;Du MQ;Calaminici M;Lister TA;Auer R;Montoto S;Gribben JG;Siebert R;Chelala C;Zoncu R;Sabatini DM;Fitzgibbon J
滤泡性淋巴瘤是一种无法治愈的B细胞恶性肿瘤，其特征是t(14；18)和表观基因组的一个或多个成分发生突变。虽然包括JAK-STAT、NOTCH和NF-κB在内的信号通路中频繁的基因突变也已被定义，但这些突变的谱通常与密切相关的弥漫性大B细胞淋巴瘤重叠。结合发现外显子组和扩展的靶向测序，发现RRAGC中反复出现的体细胞突变在FL患者中唯一丰富(17%)。超过一半的突变优先与ATP6V1B2和ATP6AP1突变共存，这两个突变是已知的空泡H+-三磷酸腺苷ATPase(v-ATPase)的组成部分，是氨基酸诱导mTORC1激活所必需的。RagC突变体增加了猛禽的结合，同时使mTORC1信号对氨基酸缺乏产生抗性。总体而言，RRAGC突变的激活性质、它们在显性克隆中的存在以及在疾病进展期间的稳定性支持了它们作为一种极好的候选药物进行治疗的潜力。
Follicular lymphoma is an incurable B-cell malignancy characterized by the t(14;18) and mutations in one or more components of the epigenome. Whilst frequent gene mutations in signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlap with the closely-related diffuse large B cell lymphoma (DLBCL). A combination of discovery exome and extended targeted sequencing revealed recurrent somatic mutations in RRAGC uniquely enriched in FL patients (17%). More than half of the mutations preferentially co-occurred with ATP6V1B2 and ATP6AP1 mutations, components of the vacuolar H+-adenosine triphosphate ATPase (v-ATPase) known to be necessary for amino acid-induced mTORC1 activation. The RagC mutants increased raptor binding whilst rendering mTORC1 signaling resistant to amino acid deprivation. Collectively, the activating nature of the RRAGC mutations, their existence within the dominant clone and stability during disease progression supports their potential as an excellent candidate to be therapeutically exploited.