The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.
The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.
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DOI：
10.1038/nm.4439
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发表时间：
2018-01
期刊：
影响因子：
82.9
通讯作者：
Meshinchi S
中科院分区：
文献类型：
--
作者：
Bolouri H;Farrar JE;Triche T Jr;Ries RE;Lim EL;Alonzo TA;Ma Y;Moore R;Mungall AJ;Marra MA;Zhang J;Ma X;Liu Y;Liu Y;Auvil JMG;Davidsen TM;Gesuwan P;Hermida LC;Salhia B;Capone S;Ramsingh G;Zwaan CM;Noort S;Piccolo SR;Kolb EA;Gamis AS;Smith MA;Gerhard DS;Meshinchi S
我们介绍了儿童急性髓性白血病（AML）的分子景观，并描述了儿童肿瘤学组（COG）AML试验的近1,000名参与者。COG-National Cancer Institute（NCI）TARGET AML倡议通过全基因组、靶向DNA、mRNA和microRNA测序以及CpG甲基化分析来评估病例。经验证的DNA变体对应于多样化的罕见突变，在>2%的病例中突变的基因少于40个。相比之下，体细胞结构变异，包括新的基因融合和MBNL 1，ZEB 2和ELF 1的局灶性缺失，在年轻个体中与成年人相比不成比例地普遍存在。相反，在成人中常见的DNMT 3A和TP 53突变在几乎所有儿科病例中明显缺失。GATA 2、FLT 3和CBL的新突变以及MYC-ITD、NRAS、KRAS和WT 1的复发突变在儿童AML中常见。缺失、突变和启动子DNA超甲基化会聚地影响Wnt信号传导、Polycomb抑制、先天免疫细胞相互作用和与KMT 2A重排相关的一簇锌指编码基因。这些结果强调了需要并促进开发针对儿童AML治疗的年龄定制靶向疗法。
We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children’s Oncology Group (COG) AML trials. The COG–National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger–encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.
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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
影响因子：
82.9
作者：
Guryanova OA;Shank K;Spitzer B;Luciani L;Koche RP;Garrett-Bakelman FE;Ganzel C;Durham BH;Mohanty A;Hoermann G;Rivera SA;Chramiec AG;Pronier E;Bastian L;Keller MD;Tovbin D;Loizou E;Weinstein AR;Gonzalez AR;Lieu YK;Rowe JM;Pastore F;McKenney AS;Krivtsov AV;Sperr WR;Cross JR;Mason CE;Tallman MS;Arcila ME;Abdel-Wahab O;Armstrong SA;Kubicek S;Staber PB;Gönen M;Paietta EM;Melnick AM;Nimer SD;Mukherjee S;Levine RL
通讯作者：
Levine RL
影响因子：
50.3
作者：
Gruber TA;Larson Gedman A;Zhang J;Koss CS;Marada S;Ta HQ;Chen SC;Su X;Ogden SK;Dang J;Wu G;Gupta V;Andersson AK;Pounds S;Shi L;Easton J;Barbato MI;Mulder HL;Manne J;Wang J;Rusch M;Ranade S;Ganti R;Parker M;Ma J;Radtke I;Ding L;Cazzaniga G;Biondi A;Kornblau SM;Ravandi F;Kantarjian H;Nimer SD;Döhner K;Döhner H;Ley TJ;Ballerini P;Shurtleff S;Tomizawa D;Adachi S;Hayashi Y;Tawa A;Shih LY;Liang DC;Rubnitz JE;Pui CH;Mardis ER;Wilson RK;Downing JR
通讯作者：
Downing JR
影响因子：
30.8
作者：
Faber ZJ;Chen X;Gedman AL;Boggs K;Cheng J;Ma J;Radtke I;Chao JR;Walsh MP;Song G;Andersson AK;Dang J;Dong L;Liu Y;Huether R;Cai Z;Mulder H;Wu G;Edmonson M;Rusch M;Qu C;Li Y;Vadodaria B;Wang J;Hedlund E;Cao X;Yergeau D;Nakitandwe J;Pounds SB;Shurtleff S;Fulton RS;Fulton LL;Easton J;Parganas E;Pui CH;Rubnitz JE;Ding L;Mardis ER;Wilson RK;Gruber TA;Mullighan CG;Schlenk RF;Paschka P;Döhner K;Döhner H;Bullinger L;Zhang J;Klco JM;Downing JR
通讯作者：
Downing JR
影响因子：
50.3
作者：
Abdel-Wahab O;Adli M;LaFave LM;Gao J;Hricik T;Shih AH;Pandey S;Patel JP;Chung YR;Koche R;Perna F;Zhao X;Taylor JE;Park CY;Carroll M;Melnick A;Nimer SD;Jaffe JD;Aifantis I;Bernstein BE;Levine RL
通讯作者：
Levine RL