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


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.

SUBMITTER: Liu Y 

PROVIDER: S-EPMC5535770 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Liu Yu Y   Easton John J   Shao Ying Y   Maciaszek Jamie J   Wang Zhaoming Z   Wilkinson Mark R MR   McCastlain Kelly K   Edmonson Michael M   Pounds Stanley B SB   Shi Lei L   Zhou Xin X   Ma Xiaotu X   Sioson Edgar E   Li Yongjin Y   Rusch Michael M   Gupta Pankaj P   Pei Deqing D   Cheng Cheng C   Smith Malcolm A MA   Auvil Jaime Guidry JG   Gerhard Daniela S DS   Relling Mary V MV   Winick Naomi J NJ   Carroll Andrew J AJ   Heerema Nyla A NA   Raetz Elizabeth E   Devidas Meenakshi M   Willman Cheryl L CL   Harvey Richard C RC   Carroll William L WL   Dunsmore Kimberly P KP   Winter Stuart S SS   Wood Brent L BL   Sorrentino Brian P BP   Downing James R JR   Loh Mignon L ML   Hunger Stephen P SP   Zhang Jinghui J   Mullighan Charles G CG  

Nature genetics 20170703 8


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, Z  ...[more]

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