The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia.
The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia.
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DOI：
10.1038/ng.3909
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发表时间：
2017-08
期刊：
影响因子：
30.8
通讯作者：
Mullighan CG
中科院分区：
文献类型：
--
作者：
Liu Y;Easton J;Shao Y;Maciaszek J;Wang Z;Wilkinson MR;McCastlain K;Edmonson M;Pounds SB;Shi L;Zhou X;Ma X;Sioson E;Li Y;Rusch M;Gupta P;Pei D;Cheng C;Smith MA;Auvil JG;Gerhard DS;Relling MV;Winick NJ;Carroll AJ;Heerema NA;Raetz E;Devidas M;Willman CL;Harvey RC;Carroll WL;Dunsmore KP;Winter SS;Wood BL;Sorrentino BP;Downing JR;Loh ML;Hunger SP;Zhang J;Mullighan CG
激活NOTCH 1信号传导和T细胞转录因子的遗传改变，加上INK 4/ARF肿瘤抑制因子的失活是T-ALL的标志，但尚未对大型T-ALL队列进行详细的全基因组测序。通过对264例T-ALL病例的整合基因组分析，我们确定了106个推定的驱动基因，其中一半以前在儿童T-ALL中没有描述过（例如CCND 3，CTCF，MYB，SMARCA 4，ZFP 36 L2和MYCN）。我们描述了编码和非编码改变的新机制，并确定了10个反复改变的途径，突变基因和途径之间的关联，T-ALL的阶段或亚型。例如，NRAS/FLT 3突变与未成熟的T-ALL相关，JAK 3/STAT 5 B突变与HOX 1失调的ALL相关，PTPN 2突变与TLX 1 T-ALL相关，PIK 3R 1/PTEN突变与TAL 1 ALL相关，这表明不同的信号通路根据成熟阶段具有不同的作用。这一基因组景观为开发可靠的遗传模型和新的治疗方法提供了一个逻辑框架。
Genetic alterations activating NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors are hallmarks of T-ALL, but detailed genome-wide sequencing of large T-ALL cohorts has not been performed. Using integrated genomic analysis of 264 T-ALL cases, we identify 106 putative driver genes, half of which were not previously described in childhood T-ALL (e.g. CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We described new mechanisms of coding and non-coding alteration, and identify 10 recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOX1 deregulated ALL, PTPN2 mutations in TLX1 T-ALL, and PIK3R1/PTEN mutations in TAL1 ALL, suggesting that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1126/science.1243292
发表时间：
2013-11-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Angulo I;Vadas O;Garçon F;Banham-Hall E;Plagnol V;Leahy TR;Baxendale H;Coulter T;Curtis J;Wu C;Blake-Palmer K;Perisic O;Smyth D;Maes M;Fiddler C;Juss J;Cilliers D;Markelj G;Chandra A;Farmer G;Kielkowska A;Clark J;Kracker S;Debré M;Picard C;Pellier I;Jabado N;Morris JA;Barcenas-Morales G;Fischer A;Stephens L;Hawkins P;Barrett JC;Abinun M;Clatworthy M;Durandy A;Doffinger R;Chilvers ER;Cant AJ;Kumararatne D;Okkenhaug K;Williams RL;Condliffe A;Nejentsev S
通讯作者：
Nejentsev S
影响因子：
4.5
作者：
Atak ZK;Gianfelici V;Hulselmans G;De Keersmaecker K;Devasia AG;Geerdens E;Mentens N;Chiaretti S;Durinck K;Uyttebroeck A;Vandenberghe P;Wlodarska I;Cloos J;Foà R;Speleman F;Cools J;Aerts S
通讯作者：
Aerts S
影响因子：
20.3
作者：
Gutierrez, Alejandro;Sanda, Takaomi;Look, A. Thomas
通讯作者：
Look, A. Thomas
影响因子：
56.9
作者：
Galloway, Alison;Saveliev, Alexander;Turner, Martin
通讯作者：
Turner, Martin