The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.

Creator(s)

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

Document Type

Article

Publication Date

1-2018

Identifier

DOI: 10.1038/nm.4439; PMCID: PMC5907936

Abstract

We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger-encoding 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.

Journal Title

Nature medicine

Volume

24

Issue

1

First Page

103

Last Page

112

MeSH Keywords

Child; Chromosome Aberrations; DNA Methylation; Humans; Leukemia, Myeloid, Acute; Mutation; Transcriptome

Keywords

Child; Chromosome Aberrations; DNA Methylation; Humans; Leukemia, Myeloid, Acute; Mutation; Transcriptome

Comments

Erratum in

• Erratum: The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Bolouri H, Farrar JE, Triche T Jr, Ries RE, Lim EL, Alonzo TA, Ma Y, Moore R, Mungall AJ, Marra MA, Zhang J, Ma X, Liu Y, Liu Y, Auvil JMG, Davidsen TM, Gesuwan P, Hermida LC, Salhia B, Capone S, Ramsingh G, Zwaan CM, Noort S, Piccolo SR, Kolb EA, Gamis AS, Smith MA, Gerhard DS, Meshinchi S.Nat Med. 2018 Apr 10;24(4):526. doi: 10.1038/nm0418-526b.PMID: 29634680
• Publisher Correction: The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Bolouri H, Farrar JE, Triche T Jr, Ries RE, Lim EL, Alonzo TA, Ma Y, Moore R, Mungall AJ, Marra MA, Zhang J, Ma X, Liu Y, Liu Y, Auvil JMG, Davidsen TM, Gesuwan P, Hermida LC, Salhia B, Capone S, Ramsingh G, Zwaan CM, Noort S, Piccolo SR, Kolb EA, Gamis AS, Smith MA, Gerhard DS, Meshinchi S.Nat Med. 2019 Mar;25(3):530. doi: 10.1038/s41591-019-0369-7.PMID: 30705421 Free PMC article.

Recommended Citation

Bolouri H, Farrar JE, Triche T Jr, et al. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions [published correction appears in Nat Med. 2018 Apr 10;24(4):526] [published correction appears in Nat Med. 2019 Mar;25(3):530]. Nat Med. 2018;24(1):103-112. doi:10.1038/nm.4439