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Cited by 918Acute Lymphoblastic Leukemia researchAcute Myeloid Leukemia ResearchLymphoma Diagnosis and Treatment

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

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Liu, Yu, Easton, John, Shao, Ying, Maciaszek, Jamie, Wang, Zhaoming, Wilkinson, Mark R, McCastlain, Kelly, Edmonson, Michael +31 more·2017·Nature Genetics
DOI 10.1038/ng.3909PMC PMC5535770
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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.

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  • Three groups of gain-of-function mutations affecting TAL1 in T-ALL-a cluster of 5′ neo-enhancer mutations upstream of TAL1 TSS, an intronic SNV and a 3′ neo-enhancer-converge on a common mechanism of upregulation of the TAL1 oncogene.

    “We evaluated three groups of gain-of-function mutations affecting the TAL1 gene in T cell acute lymphoblastic leukaemia (T-ALL): a cluster of 5′ neo-enhancer mutations upstream of the TAL1 TSS6,33, an intronic single-nucleotide variant (SNV)34 and a 3′ neo-enhancer35.”

    From Advancing regulatory variant effect prediction with AlphaGenome (2026) · cites this paper as [33]

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Cited by

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Authors
Liu, Y., Easton, J., Shao, Y., Maciaszek, J., Wang, Z., Wilkinson, M. R., McCastlain, K., Edmonson, M., Pounds, S. B., Shi, L., Zhou, X., Ma, X., Sioson, E., Li, Y., Rusch, M., Gupta, P., Pei, D., Cheng, C., Smith, M. A., Guidry Auvil, J. M., Gerhard, D. S., Relling, M. V., Winick, N. J., Carroll, A. J., Heerema, N. A., Raetz, E., Devidas, M., Willman, C. L., Harvey, R. C., Carroll, W. L., Dunsmore, K. P., Winter, S. S., Wood, B. L., Sorrentino, B. P., Downing, J. R., Loh, M. L., Hunger, S. P., Zhang, J., & Mullighan, C. G.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • National Institutes of Health (US)
  • The University of Texas Southwestern Medical Center (US)
  • University of Alabama at Birmingham (US)
  • The Ohio State University (US)
  • Primary Children's Hospital (US)
  • University of Florida Health (US)
  • University of New Mexico (US)
  • NYU Langone Health (US)
  • University of Virginia (US)
  • Seattle Cancer Care Alliance (US)
  • University of California, San Francisco (US)
  • Children's Hospital of Philadelphia (US)
Corresponding author
  • Hunger, Stephen P
  • Zhang, Jinghui
  • Mullighan, Charles G
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2017-07-03
Volume
49
Issue
8
Pages
1211-1218
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.3909
PMC
PMC5535770
OpenAlex
W2733265822
Cited by
918
References
9
Citations by year
2026: 39 · 2025: 73 · 2024: 110 · 2023: 130 · 2022: 125 · 2021: 131 · 2020: 113 · 2019: 99 · 2018: 79 · 2017: 16 · 2012: 1
FWCI
78.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (HHSN261200800001C)
  • National Cancer Institute (U10CA098413, U24CA114766, HHSN261200800001E), RC2CA148529, U10CA180899, U01CA157937, U10CA098543, P30CA016058, R35CA197695, P30CA021765)
  • National Institute of General Medical Sciences (P50GM115279)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
Keywords
T-cell acute lymphoblastic leukemia, pediatric leukemia, young adult leukemia, driver genes, Notch1 signaling, T cell transcription factors, TLX1, TAL1, MYCN, cyclin D3, CTCF, SMARCA4, ZFP36L2, MYB, disease subtypes
MeSH terms
Adolescent, Adult, Child, Child, Preschool, Humans, Middle Aged, Mutation, Gene Rearrangement, Cohort Studies, Signal Transduction, Gene Expression Regulation, Neoplastic, Cell Lineage, Genomics, Epigenesis, Genetic, Receptor, Notch1, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Young Adult

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