The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias

被引：401

作者：

Andersson, Anna K. ^{[1
,2
]}

Ma, Jing ^{[1
]}

Wang, Jianmin ^{[3
]}

Chen, Xiang ^{[3
]}

Gedman, Amanda Larson ^{[1
]}

Dang, Jinjun ^{[1
]}

Nakitandwe, Joy ^{[1
]}

Holmfeldt, Linda ^{[1
]}

Parker, Matthew ^{[3
]}

Easton, John ^{[4
]}

Huether, Robert ^{[3
]}

Kriwacki, Richard ^{[5
]}

Rusch, Michael ^{[3
]}

Wu, Gang ^{[3
]}

Li, Yongjin ^{[3
]}

Mulder, Heather ^{[4
]}

Raimondi, Susana ^{[1
]}

Pounds, Stanley ^{[6
]}

Kang, Guolian ^{[6
]}

Shi, Lei ^{[6
]}

Becksfort, Jared ^{[3
]}

Gupta, Pankaj ^{[3
]}

Payne-Turner, Debbie ^{[1
]}

Vadodaria, Bhavin ^{[4
]}

Boggs, Kristy ^{[4
]}

Yergeau, Donald ^{[4
]}

Manne, Jayanthi ^{[4
]}

Song, Guangchun ^{[1
]}

Edmonson, Michael ^{[3
]}

Nagahawatte, Panduka ^{[3
]}

Wei, Lei ^{[3
]}

Cheng, Cheng ^{[6
]}

Pei, Deqing ^{[6
]}

Sutton, Rosemary ^{[7
]}

Venn, Nicola C. ^{[7
]}

Chetcuti, Albert ^{[8
]}

Rush, Amanda ^{[8
]}

Catchpoole, Daniel ^{[8
]}

Heldrup, Jesper ^{[9
]}

Fioretos, Thoas ^{[2
]}

Lu, Charles ^{[10
,11
]}

Ding, Li ^{[10
,11
]}

Pui, Ching-Hon ^{[1
,12
]}

Shurtleff, Sheila ^{[1
]}

Mullighan, Charles G. ^{[1
]}

Mardis, Elaine R. ^{[10
,11
]}

Wilson, Richard K. ^{[10
,11
]}

Gruber, Tanja A. ^{[1
,12
]}

Zhang, Jinghui ^{[3
]}

Downing, James R. ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[2] Lund Univ, Dept Clin Genet, Lund, Sweden

[3] St Jude Childrens Res Hosp, Dept Computat Biol, Memphis, TN 38105 USA

[4] St Jude Childrens Res Hosp, Pediat Canc Genome Project Lab, Memphis, TN 38105 USA

[5] St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA

[6] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA

[7] Univ New S Wales, Lowy Canc Res Ctr, Childrens Canc Inst Australia, Sydney, NSW, Australia

[8] Childrens Hosp Westmead, Tumor Bank, Childrens Canc Res Unit, Sydney, NSW, Australia

[9] Skane Univ Hosp, Dept Pediat, Lund, Sweden

[10] Washington Univ, Sch Med St Louis, Dept Genet, St Louis, MO USA

[11] Washington Univ, Sch Med St Louis, Genome Inst, St Louis, MO USA

[12] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA

来源：

NATURE GENETICS | 2015年 / 47卷 / 04期

基金：

瑞典研究理事会; 美国国家卫生研究院;

关键词：

ACUTE MYELOID-LEUKEMIA; K-RAS MUTATIONS; CHROMOSOMAL TRANSLOCATIONS; GENETIC ALTERATIONS; CANCER; IDENTIFICATION; RESISTANCE; T(4/11); FLT3; BREAKPOINT;

D O I：

10.1038/ng.3230

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 x 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.

引用

页码：330 / U192

页数：11

共 69 条

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Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement [J].