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Nat Genet. 2016 May;48(5):569-74. doi: 10.1038/ng.3535. Epub 2016 Mar 28.

Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults.

Author information

1
Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
2
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Aichi, Japan.
3
Division of Molecular Medicine, Aichi Cancer Center Research Institute, Aichi, Japan.
4
Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
5
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
6
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
7
Leukemia Research Center, Saiseikai Maebashi Hospital, Gunma, Japan.
8
Third Department of Internal Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
9
Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
10
Department of Hematology, Fujisawa City Hospital, Kanagawa, Japan.
11
Department of Hematology/Oncology, Kurashiki Central Hospital, Okayama, Japan.
12
Department of Internal Medicine, Seichoukai Fuchu Hospital, Osaka, Japan.
13
Department of Clinical Laboratory Science, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
14
Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
15
Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
16
Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
17
Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
18
National Hospital Organization Nagoya Medical Center, Aichi, Japan.

Abstract

The oncogenic mechanisms underlying acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA; 15-39 years old) remain largely elusive. Here we have searched for new oncogenes in AYA-ALL by performing RNA-seq analysis of Philadelphia chromosome (Ph)-negative AYA-ALL specimens (n = 73) with the use of a next-generation sequencer. Interestingly, insertion of D4Z4 repeats containing the DUX4 gene into the IGH locus was frequently identified in B cell AYA-ALL, leading to a high level of expression of DUX4 protein with an aberrant C terminus. A transplantation assay in mice demonstrated that expression of DUX4-IGH in pro-B cells was capable of generating B cell leukemia in vivo. DUX4 fusions were preferentially detected in the AYA generation. Our data thus show that DUX4 can become an oncogenic driver as a result of somatic chromosomal rearrangements and that AYA-ALL may be a clinical entity distinct from ALL at other ages.

PMID:
27019113
DOI:
10.1038/ng.3535
[Indexed for MEDLINE]

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