title: Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults.
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.
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Aichi, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Aichi, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Tsuzuki
authors.affiliation: Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Kawazu
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Aichi, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hayakawa
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kojima
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Aichi, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Imoto
authors.affiliation: Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kohsaka
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kunita
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Doi
authors.affiliation: Leukemia Research Center, Saiseikai Maebashi Hospital, Gunma, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Sakura
authors.affiliation: Third Department of Internal Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Yujiri
authors.affiliation: Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Eisei
authors.initials: E
authors.lastname: Kondo
authors.affiliation: Department of Hematology, Fujisawa City Hospital, Kanagawa, Japan.
authors.forename: Katsumichi
authors.initials: K
authors.lastname: Fujimaki
authors.affiliation: Department of Hematology/Oncology, Kurashiki Central Hospital, Okayama, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of Internal Medicine, Seichoukai Fuchu Hospital, Osaka, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Aoyama
authors.affiliation: Department of Clinical Laboratory Science, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Ohtake
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Takita
authors.affiliation: Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Eirin
authors.initials: E
authors.lastname: Sai
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Morishita
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Aichi, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
authors.affiliation: Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: National Hospital Organization Nagoya Medical Center, Aichi, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D050939:Gene Fusion; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D064326:MEF2 Transcription Factors / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012334:RNA, Neoplasm; D017423:Sequence Analysis, RNA; D015534:Trans-Activators / Q000235:genetics; D055815:Young Adult
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D007143:Immunoglobulin Heavy Chains; D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; D015514:Oncogene Proteins, Fusion; D012334:RNA, Neoplasm; D015534:Trans-Activators; C498621:ZNF384 protein, human