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

• Published in: Nature genetics Vol. 48; no. 5; pp. 569 - 574
• Main Authors: Yasuda, Takahiko, Tsuzuki, Shinobu, Kawazu, Masahito, Hayakawa, Fumihiko, Kojima, Shinya, Ueno, Toshihide, Imoto, Naoto, Kohsaka, Shinji, Kunita, Akiko, Doi, Koichiro, Sakura, Toru, Yujiri, Toshiaki, Kondo, Eisei, Fujimaki, Katsumichi, Ueda, Yasunori, Aoyama, Yasutaka, Ohtake, Shigeki, Takita, Junko, Sai, Eirin, Taniwaki, Masafumi, Kurokawa, Mineo, Morishita, Shinichi, Fukayama, Masashi, Kiyoi, Hitoshi, Miyazaki, Yasushi, Naoe, Tomoki, Mano, Hiroyuki
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2016; Nature Publishing Group
• Subjects: 38; 38/91; 45; 631/208/200; 631/208/212; 692/699/67/1990/283/2125; Acute lymphocytic leukemia; Adolescent; Adolescents; Adult; Age; Age Factors; Aged; Aged, 80 and over; Agriculture; Animal Genetics and Genomics; Animals; Archives & records; Biomedicine; Cancer; Cancer Research; Child; Child, Preschool; Chromosomes; Cohort Studies; Development and progression; Female; Gene expression; Gene Function; Gene Fusion; Genetic aspects; Genomes; Genotype & phenotype; HEK293 Cells; Homeodomain Proteins - genetics; Human Genetics; Humans; Identification and classification; Immunoglobulin Heavy Chains - genetics; Infant; Infant, Newborn; Kinases; letter; Leukemia; Male; Medical prognosis; MEF2 Transcription Factors - genetics; Mice; Middle Aged; Mutation; NIH 3T3 Cells; Oncogene Proteins, Fusion; Oncogenes; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Proteins; R&D; Research & development; RNA, Neoplasm; Sequence Analysis, RNA; Studies; Trans-Activators - genetics; Young Adult; Young adults
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3535

Hiroyuki Mano and colleagues report fusions involving
DUX4
in 16.4% of Ph-negative adolescent and young adult acute lymphoblastic leukemia (AYA-ALL) cases. Transplantation assays in mice support an oncogenic role for the
DUX4-IGH
fusion gene, which expresses DUX4 protein with an aberrant C terminus at high levels in patients with AYA-ALL.
The oncogenic mechanisms underlying acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA; 15–39 years old) remain largely elusive
1
,
2
,
3
. 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.