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

Research output: Contribution to journalArticle

69 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
JournalNature Genetics
DOIs
Publication statusAccepted/In press - Mar 28 2016

Fingerprint

Precursor Cell Lymphoblastic Leukemia-Lymphoma
Young Adult
B-Lymphocytes
B-Cell Leukemia
Philadelphia Chromosome
B-Lymphoid Precursor Cells
Oncogenes
Transplantation
RNA
Genes
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Yasuda, T., Tsuzuki, S., Kawazu, M., Hayakawa, F., Kojima, S., Ueno, T., ... Mano, H. (Accepted/In press). Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults. Nature Genetics. https://doi.org/10.1038/ng.3535

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

In: Nature Genetics, 28.03.2016.

Research output: Contribution to journalArticle

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, Taniwaki, M, Kurokawa, M, Morishita, S, Fukayama, M, Kiyoi, H, Miyazaki, Y, Naoe, T & Mano, H 2016, 'Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults', Nature Genetics. https://doi.org/10.1038/ng.3535
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. / Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults. In: Nature Genetics. 2016.
@article{bdfa081756574c41b8efc594f34975d0,
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.",
author = "Takahiko Yasuda and Shinobu Tsuzuki and Masahito Kawazu and Fumihiko Hayakawa and Shinya Kojima and Toshihide Ueno and Naoto Imoto and Shinji Kohsaka and Akiko Kunita and Koichiro Doi and Toru Sakura and Toshiaki Yujiri and Eisei Kondo and Katsumichi Fujimaki and Yasunori Ueda and Yasutaka Aoyama and Shigeki Ohtake and Junko Takita and Eirin Sai and Masafumi Taniwaki and Mineo Kurokawa and Shinichi Morishita and Masashi Fukayama and Hitoshi Kiyoi and Yasushi Miyazaki and Tomoki Naoe and Hiroyuki Mano",
year = "2016",
month = "3",
day = "28",
doi = "10.1038/ng.3535",
language = "English",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults

AU - Yasuda, Takahiko

AU - Tsuzuki, Shinobu

AU - Kawazu, Masahito

AU - Hayakawa, Fumihiko

AU - Kojima, Shinya

AU - Ueno, Toshihide

AU - Imoto, Naoto

AU - Kohsaka, Shinji

AU - Kunita, Akiko

AU - Doi, Koichiro

AU - Sakura, Toru

AU - Yujiri, Toshiaki

AU - Kondo, Eisei

AU - Fujimaki, Katsumichi

AU - Ueda, Yasunori

AU - Aoyama, Yasutaka

AU - Ohtake, Shigeki

AU - Takita, Junko

AU - Sai, Eirin

AU - Taniwaki, Masafumi

AU - Kurokawa, Mineo

AU - Morishita, Shinichi

AU - Fukayama, Masashi

AU - Kiyoi, Hitoshi

AU - Miyazaki, Yasushi

AU - Naoe, Tomoki

AU - Mano, Hiroyuki

PY - 2016/3/28

Y1 - 2016/3/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84961875103&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84961875103&partnerID=8YFLogxK

U2 - 10.1038/ng.3535

DO - 10.1038/ng.3535

M3 - Article

C2 - 27019113

AN - SCOPUS:84961875103

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -