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

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

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89 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)569-574
Number of pages6
JournalNature Genetics
Volume48
Issue number5
DOIs
Publication statusPublished - May 1 2016

ASJC Scopus subject areas

  • Genetics

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    Yasuda, T., Tsuzuki, S., Kawazu, M., Hayakawa, F., Kojima, S., Ueno, T., Imoto, N., Kohsaka, S., Kunita, A., Doi, K., Sakura, T., Yujiri, T., Kondo, E., Fujimaki, K., Ueda, Y., Aoyama, Y., Ohtake, S., Takita, J., Sai, E., ... Mano, H. (2016). Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults. Nature Genetics, 48(5), 569-574. https://doi.org/10.1038/ng.3535