The genomic landscape of hypodiploid acute lymphoblastic leukemia

被引：507

作者：

Holmfeldt, Linda ^{[1
]}

Wei, Lei ^{[1
]}

Diaz-Flores, Ernesto ^{[2
]}

Walsh, Michael ^{[3
]}

Zhang, Jinghui ^{[4
]}

Ding, Li ^{[5
,6
]}

Payne-Turner, Debbie ^{[1
]}

Churchman, Michelle ^{[1
]}

Andersson, Anna ^{[1
,7
]}

Chen, Shann-Ching ^{[1
]}

McCastlain, Kelly ^{[1
]}

Becksfort, Jared ^{[4
]}

Ma, Jing ^{[1
]}

Wu, Gang ^{[4
]}

Patel, Samir N. ^{[1
]}

Heatley, Susan L. ^{[1
]}

Phillips, Letha A. ^{[1
]}

Song, Guangchun ^{[1
]}

Easton, John ^{[8
]}

Parker, Matthew ^{[4
]}

Chen, Xiang ^{[4
]}

Rusch, Michael ^{[4
]}

Boggs, Kristy ^{[8
]}

Vadodaria, Bhavin ^{[8
]}

Hedlund, Erin ^{[4
]}

Drenberg, Christina ^{[9
]}

Baker, Sharyn ^{[9
]}

Pei, Deqing ^{[10
]}

Cheng, Cheng ^{[10
]}

Huether, Robert ^{[4
]}

Lu, Charles ^{[5
]}

Fulton, Robert S. ^{[5
,6
]}

Fulton, Lucinda L. ^{[5
,6
]}

Tabib, Yashodhan ^{[5
]}

Dooling, David J. ^{[5
,6
]}

Ochoa, Kerri ^{[5
]}

Minden, Mark ^{[11
]}

Lewis, Ian D. ^{[12
]}

To, L. Bik ^{[12
]}

Marlton, Paula ^{[13
]}

Roberts, Andrew W. ^{[14
]}

Raca, Gordana ^{[15
]}

Stock, Wendy ^{[15
]}

Neale, Geoffrey ^{[16
]}

Drexler, Hans G. ^{[17
]}

Dickins, Ross A. ^{[18
]}

Ellison, David W. ^{[1
]}

Shurtleff, Sheila A. ^{[1
]}

Pui, Ching-Hon ^{[3
]}

Ribeiro, Raul C. ^{[3
]}

机构：

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

[2] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA

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

[4] St Jude Childrens Res Hosp, Dept Computat Biol & Bioinformat, Memphis, TN 38105 USA

[5] Washington Univ, Genome Inst, St Louis, MO USA

[6] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[7] Univ Lund Hosp, Dept Clin Genet, S-22185 Lund, Sweden

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

[9] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA

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

[11] Univ Toronto, Princess Margaret Hosp, Univ Hlth Network, Toronto, ON M5S 1A1, Canada

[12] Inst Med & Vet Sci, Div Haematol, Adelaide, SA 5000, Australia

[13] Princess Alexandra Hosp, Oncol Haematol Unit, Woolloongabba, Qld 4102, Australia

[14] Royal Melbourne Hosp, Dept Clin Haematol & Bone Marrow Transplant, Melbourne, Vic, Australia

[15] Univ Chicago Med, Sect Hematol Oncol, Chicago, IL USA

[16] St Jude Childrens Res Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA

[17] Deutsch Sammlung Mikroorganismen & Zellkulturen, Dept Human & Anim Cell Cultures, Braunschweig, Germany

[18] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Mol Med Div, Parkville, Vic 3050, Australia

[19] Univ Florida, Coll Med, Dept Biostat, Gainesville, FL USA

[20] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA

[21] Ohio State Univ, Ctr Comprehens Canc, Coll Med, Dept Pathol, Columbus, OH 43210 USA

[22] Seattle Childrens Hosp, Dept Lab Med, Seattle, WA USA

[23] Johns Hopkins Univ Hosp, Div Hematol Pathol, Baltimore, MD 21287 USA

[24] Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH USA

[25] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA

[26] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA

[27] Washington Univ, Siteman Canc Ctr, St Louis, MO USA

[28] Univ Colorado, Denver Sch Med, Childrens Hosp Colorado, Sect Pediat Hematol Oncol Bone Marrow Transplanta, Aurora, CO USA

[29] Univ Colorado, Denver Sch Med, Childrens Hosp Colorado, Ctr Canc & Blood Disorders, Aurora, CO USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 03期

基金：

瑞典研究理事会; 美国国家卫生研究院;

关键词：

JUVENILE MYELOMONOCYTIC LEUKEMIA; NEUROFIBROMATOSIS TYPE-1 GENE; REGULATORY T-CELLS; TRANSMEMBRANE ADAPTER; HEMATOLOGIC MALIGNANCIES; P53; MUTATIONS; HUMAN CANCERS; MUTANT P53; IKAROS; CHILDHOOD;

D O I：

10.1038/ng.2532

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.

引用

页码：242 / 252

页数：11

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