Journal Article

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

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

2017

Overview

Charles Mullighan, Stephen Hunger, Jinghui Zhang and colleagues report a genomic analysis of 264 pediatric and young adult T-lineage acute lymphoblastic leukemia (T-ALL) samples. They identify 106 candidate driver genes, 53 of which have not been described previously in pediatric T-ALL, as well as associations between mutations and disease stage or subtype. 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.

• Publisher: Springer New York,Nature Publishing Group
• Subject: 38/39 / 45/23 / 45/61 / 45/77 / 45/91 / 631/114/2785 / 631/67/1990/283/2125 / 64/60 / 692/699/67/1990/283/2125 / Acute lymphoblastic leukemia / Acute lymphocytic leukemia / Adolescent / Adult / Agriculture / Analysis / Animal Genetics and Genomics / Biomedicine / Cancer Research / Cell Lineage / Child / Child, Preschool / Children / Cohort Studies / Cyclin-dependent kinase inhibitors / Deactivation / Deregulation / Development and progression / Epigenesis, Genetic / Gene Expression Regulation, Neoplastic / Gene Function / Gene Rearrangement / Gene sequencing / Genes / Genetic aspects / Genomes / Genomic analysis / Genomics / HOXA1 protein / Human Genetics / Humans / Inactivation / INK4 protein / Kinases / Leukemia / Lymphatic leukemia / Lymphocytes T / Middle Aged / Mutation / Notch1 protein / Physiological aspects / Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics / PTEN protein / PTPN2 protein / Receptor, Notch1 - metabolism / Signal transduction / Signal Transduction - genetics / Suppressors / T cell receptors / T cells / Tlx1 protein / Transcription factors / Young Adult / Young adults