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

Yu Liu, John Easton, Ying Shao, Jamie Maciaszek, Zhaoming Wang, Mark R. Wilkinson, Kelly McCastlain, Michael Edmonson, Stanley B. Pounds, Lei Shi, Xin Zhou, Xiaotu Ma, Edgar Sioson, Yongjin Li, Michael Rusch, Pankaj Gupta, Deqing Pei, Cheng Cheng, Malcolm A. Smith, Jaime Guidry AuvilDaniela S. Gerhard, Mary V. Relling, Naomi J. Winick, Andrew J. Carroll, Nyla A. Heerema, Elizabeth Raetz, Meenakshi Devidas, Cheryl L. Willman, Richard C. Harvey, William L. Carroll, Kimberly P. Dunsmore, Stuart S. Winter, Brent L. Wood, Brian P. Sorrentino, James R. Downing, Mignon L. Loh, Stephen P. Hunger, Jinghui Zhang, Charles G. Mullighan

Research output: Contribution to journalArticle

215 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1211-1218
Number of pages8
JournalNature genetics
Volume49
Issue number8
DOIs
StatePublished - Aug 1 2017

ASJC Scopus subject areas

  • Genetics

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