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

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.

Journal: Nature genetics
DOI: 10.1038/ng.3535
Year: 2016

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