並列タイトル等RLTPR Q575E : A novel recurrent gain-of-function mutation in patients with adult T-cell leukemia/lymphoma
学位博士(医学)
Doctor of Philosophy in Medical Science
一般注記博士論文全文, 博士論文要旨, 最終試験結果の要旨, 論文審査の要旨
Objectives: Adult T-cell leukemia/lymphoma (ATL) is an intractable T-cell malignancy caused by long-term infection with human T-cell leukemia virus type-1 (HTLV-1). While ATL pathogenesis has been associated with HTLV-1-derived oncogenic proteins, including Tax and HBZ, the contribution of genomic aberrations remains poorly defined.Methods: To elucidate the genomic basis of ATL, whole exome sequencing was performed on cells from 47 patients with aggressive ATL.Results: We discovered the novel mutation RLTPR Q575E in four patients (8.5%) with a median variant allele frequency of 0.52 (range 0.11-0.68). Despite being reported in cutaneous T-cell lymphoma, three ATL patients carrying RLTPR Q575E lacked skin involvement. Patients carrying RLTPR Q575E also harbored CARD11 (75%), PLCG1 (25%), PRKCB (25%), or IKBKB (25%) mutations related to TCR/NF-κB signaling. Jurkat cells transfected with RLTPR Q575E cDNA displayed increased NF-κB activity and significantly increased IL-2 mRNA levels under stimulation. RLTPR Q575E increased the interaction between RLTPR and CARD11, while RLTPR directly interacted with Tax.Conclusions: We identified, and functionally validated, a novel gain-of-function mutation in patients with aggressive ATL. During TCR activation by Tax or gain-of-function mutations, RLTPR Q575E selectively upregulates NF-κB signaling and may exert oncogenic effects on ATL pathogenesis.This is the peer reviewed version of the following article:Yuichiro Uchida, Makoto Yoshimitsu, Miho Hachiman, Shuichi Kusano, Naosuke Arima, Kodai Shima, Maiko Hayashida, Yuhei Kamada, Daisuke Nakamura, Akihiko Arai, Yuetsu Tanaka, Hiromitsu Hara, Kenji IshitsukaRLTPR Q575E: A novel recurrent gain-of-function mutation in patients with adult T-cell leukemia/lymphomaEuropean Journal of Haematology (2021), 106(2), 221–229© 2020 John Wiley & Sons A/S.which has been published in final form at https://doi.org/10.1111/ejh.13540This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.
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受理日（W3CDTF）2022-08-08T06:02:54+09:00
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