Journal Article

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

Sai, Eirin, Fukayama, Masashi, Doi, Koichiro, Kondo, Eisei, Yujiri, Toshiaki, Taniwaki, Masafumi, Kiyoi, Hitoshi, Kojima, Shinya, Kurokawa, Mineo, Ohtake, Shigeki, Ueda, Yasunori, Yasuda, Takahiko, Kawazu, Masahito, Hayakawa, Fumihiko, Morishita, Shinichi, Kohsaka, Shinji, Kunita, Akiko, Sakura, Toru, Tsuzuki, Shinobu, Mano, Hiroyuki, Ueno, Toshihide, Miyazaki, Yasushi, Aoyama, Yasutaka, Takita, Junko, Imoto, Naoto, Naoe, Tomoki, Fujimaki, Katsumichi

2016

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 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