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Nat Genet. 2017 Aug;49(8):1211-1218. doi: 10.1038/ng.3909. Epub 2017 Jul 3.

The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia.

Author information

1
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
2
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
3
Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
4
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
5
Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA.
6
Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland, USA.
7
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
8
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
9
Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
10
Department of Pathology, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
11
Department of Pediatrics, Huntsman Cancer Institute and Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA.
12
Department of Biostatistics, Colleges of Medicine, Public Health &Health Profession, University of Florida, Gainesville, Florida, USA.
13
Department of Pathology, The Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico, USA.
14
Department of Pediatrics, Perlmutter Cancer Center, New York University Medical Center, New York, New York, USA.
15
Health Sciences Center, University of Virginia, Charlottesville, Virginia, USA.
16
Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico, USA.
17
Seattle Cancer Care Alliance, Seattle, Washington, USA.
18
Department of Pediatrics, Benioff Children's Hospital, University of California at San Francisco, San Francisco, California, USA.
19
Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Abstract

Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten 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 HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests 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.

PMID:
28671688
PMCID:
PMC5535770
DOI:
10.1038/ng.3909
[Indexed for MEDLINE]
Free PMC Article

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