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Nat Genet. 2017 Mar;49(3):451-456. doi: 10.1038/ng.3772. Epub 2017 Jan 23.

Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes.

Author information

1
Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
2
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
3
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
4
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
5
Department of Pediatric Hematology/Oncology, Medical School Hannover, Hannover, Germany.
6
Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
7
Department of Pediatric Oncology, University of Duisburg-Essen, Essen, Germany.
8
Department of Women's and Children's Health, University of Padova, Padova, Italy.
9
Cancer Science Institute, National University of Singapore, Singapore.
10
Chang Gung Memorial Hospital-Linkou, Chang Gung University, Taoyuan City, Taiwan.
11
Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan.
12
Section of Hematology, Department of Internal Medicine and Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA.
13
Department of Laboratory Medicine, Yale University, New Haven, Connecticut, USA.
14
Department of Pediatric Hematology Oncology, University of Pavia, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
15
Department of Pediatric Oncology, Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.

Abstract

Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A. However, the etiology of 30-40% of cases remains unknown. To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult). We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes. Overall, these data shed light on the etiology of AMKL and provide useful information for the tailoring of treatment.

PMID:
28112737
PMCID:
PMC5687824
DOI:
10.1038/ng.3772
[Indexed for MEDLINE]
Free PMC Article

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