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Nat Genet. 2019 Apr;51(4):694-704. doi: 10.1038/s41588-019-0375-1. Epub 2019 Mar 29.

Genomic subtyping and therapeutic targeting of acute erythroleukemia.

Author information

1
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
2
MLL Munich Leukemia Laboratory, Munich, Germany.
3
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
4
The Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
6
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
7
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
8
Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
9
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
10
Cytogenetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN, USA.
11
Clinic of Paediatric Haematology and Oncology, Department for Children's and Women's Health, University of Padua, Padua, Italy.
12
Italian Institute for Genomic Medicine, Turin, Italy.
13
Department of Gynecology/Obstetrics and Pediatrics, Sapienza University of Rome, Rome, Italy.
14
Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
15
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
16
Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
17
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
18
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
19
Department of Pediatrics, Benioff Children's Hospital, and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
20
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
21
Department of Clinical Haematology, The Alfred Hospital, Melbourne, Victoria, Australia.
22
Department of Pathology, The Alfred Hospital, Melbourne, Victoria, Australia.
23
Departments of Haematology, SA Pathology and Royal Adelaide Hospital, Adelaide, South Australia, Australia.
24
Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.
25
Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
26
The Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
27
Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
28
Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia.
29
Princess Alexandra Hospital and University of Queensland School of Clinical Medicine, Brisbane, Queensland, Australia.
30
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA. charles.mullighan@stjude.org.

Abstract

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.

PMID:
30926971
DOI:
10.1038/s41588-019-0375-1
[Indexed for MEDLINE]

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