Paper

Comprehensive characterization of pediatric AML reveals diverse fusion oncoproteins and age-specific mutational interactions

Noort, Sanne, Liu, Yanling, Ries, Rhonda E, Ma, Xiaotu, Mungall, Andrew, Lim, Emilia L, Bolouri, Hamid, Marra, Marco A, Salhia, Bodour, Zhang, Jinghui, Hermida, Leandro C, Davidsen, Tanja M, Gamis, Alan S, Moore, Richard, Guidry Auvil, Jaime M, Piccolo, Stephen, Farrar, Jason E, Liu, Yu, Alonzo, Todd A, Cm Michel Zwaan, Meshinchi, Soheil, Giridharan Ramsingh, Ma, Yussanne, Kolb, E Anders, Capone, Stephen, Smith, Malcolm A, Gerhard, Daniela S, Triche, Tim J, Gesuwan, Patee

2017

Overview

We present the molecular landscape of pediatric acute myeloid leukemia (AML), characterizing nearly 1,000 participants in Childrens Oncology Group (COG) AML trials. The COG/NCI TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA, miRNA sequencing and CpG methylation profiling. Validated DNA variants revealed diverse, infrequent mutations with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including novel gene fusions and focal MBNL1, ZEB2, and ELF1 deletions, were disproportionately prevalent in young as compared to adult patients. Conversely, DNMT3A and TP53 mutations, common in adults, are conspicuously absent from virtually all pediatric cases. Novel GATA2, FLT3, and CBL mutations, recurrent MYC-ITD, NRAS, KRAS, and WT1 mutations are frequent in pediatric AML. Deletions, mutations, and promoter DNA hypermethylation convergently impact Wnt signaling, Polycomb repression, innate immune cell interactions, and a cluster of zinc finger genes associated with KMT2A rearrangements. These results highlight the need for, and facilitate the development of, age-tailored targeted therapies for the treatment of pediatric AML.

• Publisher: Cold Spring Harbor Laboratory Press
• Subject: Acute myeloid leukemia / Age / Cell interactions / Clinical trials / CpG islands / Deoxyribonucleic acid / DNA / DNA fingerprinting / DNA methylation / DNA sequencing / Genomes / miRNA / mRNA / Mutation / Myc protein / Myeloid leukemia / Oncoproteins / p53 Protein / Pediatrics / Polycomb group proteins / Wnt protein / Zinc finger proteins