Integrated molecular analysis of adult T cell leukemia/lymphoma

Keisuke Kataoka, Yasunobu Nagata, Akira Kitanaka, Yuichi Shiraishi, Teppei Shimamura, Jun Ichirou Yasunaga, Yasushi Totoki, Kenichi Chiba, Aiko Sato-Otsubo, Genta Nagae, Ryohei Ishii, Satsuki Muto, Shinichi Kotani, Yosaku Watatani, June Takeda, Masashi Sanada, Hiroko Tanaka, Hiromichi Suzuki, Yusuke Sato, Yusuke ShiozawaTetsuichi Yoshizato, Kenichi Yoshida, Hideki Makishima, Masako Iwanaga, Guangyong Ma, Kisato Nosaka, Masakatsu Hishizawa, Hidehiro Itonaga, Yoshitaka Imaizumi, Wataru Munakata, Hideaki Ogasawara, Toshitaka Sato, Ken Sasai, Kenzo Muramoto, Marina Penova, Takahisa Kawaguchi, Hiromi Nakamura, Natsuko Hama, Kotaro Shide, Yoko Kubuki, Tomonori Hidaka, Takuro Kameda, Tsuyoshi Nakamaki, Ken Ishiyama, Shuichi Miyawaki, Sung Soo Yoon, Kensei Tobinai, Yasushi Miyazaki, Akifumi Takaori-Kondo, Fumihiko Matsuda, Kengo Takeuchi, Osamu Nureki, Hiroyuki Aburatani, Toshiki Watanabe, Tatsuhiro Shibata, Masao Matsuoka, Satoru Miyano, Kazuya Shimoda, Seishi Ogawa

Research output: Contribution to journalArticlepeer-review

331 Citations (Scopus)

Abstract

Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF- signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.

Original languageEnglish
Pages (from-to)1304-1315
Number of pages12
JournalNature genetics
Volume47
Issue number11
DOIs
Publication statusPublished - 2015 Nov 1
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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