Authors

Hamid Bolouri, Fred Hutchinson Cancer Research Center
Jason E. Farrar, University of Arkansas for Medical Sciences
Timothy Triche Jr, University of Southern California Norris Comprehensive Cancer Center
Rhonda E. Ries, Fred Hutchinson Cancer Research Center
Emilia L. Lim, British Columbia Cancer Agency
Todd A. Alonzo, University of Southern California
Yussanne Ma, British Columbia Cancer Agency
Richard Moore, British Columbia Cancer Agency
Andrew J. Mungall, British Columbia Cancer Agency
Marco A. Marra, British Columbia Cancer Agency
Jinghui Zhang, St. Jude Children's Research Hospital
Xiaotu Ma, St. Jude Children's Research Hospital
Yu Liu, St. Jude Children's Research Hospital
Yanling Liu, St. Jude Children's Research Hospital
Jaime M. Guidry Auvil, National Cancer Institute
Tanja M. Davidsen, National Cancer Institute
Patee Gesuwan, National Cancer Institute
Leandro C. Hermida, National Cancer Institute
Bodour Salhia, University of Southern California
Stephen Capone, University of Southern California Norris Comprehensive Cancer Center
Giridharan Ramsingh, University of Southern California Norris Comprehensive Cancer Center
Christian Michel Zwaan, Erasmus MC–Sophia Children's Hospital
Sanne Noort, Erasmus MC–Sophia Children's Hospital
Stephen R. Piccolo, Brigham Young University - Provo
E. Anders Kolb, Alfred I. DuPont Hospital for Children
Alan S. Gamis, Children's Mercy Hospitals and Clinics
Malcolm A. Smith, National Cancer Institute
Daniela S. Gerhard, National Cancer Institute
Soheil Meshinchi, Fred Hutchinson Cancer Research Center

Keywords

Pediatric acute myeloid leukemia, TARGET AML initiative, CpG methylation profiling

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.

Original Publication Citation

Bolouri H, Farrar JE, Triche TJ, 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, and Meshinchi S. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nature Medicine, 2017 Dec 11. doi: 10.1038/nm.443920

Document Type

Peer-Reviewed Article

Publication Date

2017-12-11

Publisher

Nature Research

Language

English

College

Life Sciences

Department

Biology

University Standing at Time of Publication

Associate Professor

Included in

Biology Commons

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