Molecular cytogenetic studies of MYC and PVT1 rearrangements in refractory and relapsed lymphoma

• Project/Area Number: 16K09856
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Taniwaki Masafumi 京都府立医科大学, 医学(系)研究科(研究院), 特任教授 (80163640)
• Co-Investigator(Kenkyū-buntansha): 名越 久朗 京都府立医科大学, 医学部附属病院, 研究員 (80713924) ; 知念 良顕 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10757602)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 難治性リンパ腫 / 8q24染色体異常 / キメラmRNA / PVT1 / long noncoding RNA / 遺伝子増幅 / 非コード遺伝子 / PVT1遺伝子 / MYC遺伝子 / びまん性大細胞型Bリンパ腫 / 成人T細胞白血病・リンパ腫

Outline of Final Research Achievements

We have detected alteration of long noncoding RNA (lncRNA) PVT1 gene in two diffuse large B-cell lymphoma cell lines; chimeric gene in one and high-magnitude amplification in the other. Fluorescence in situ hybridization (FISH) using own two original FISH probes, PVT1-adjacent (PVT1-A) and PVT1-spanning (PVT1-S), demonstrated a breakpoint of the chimeric gene around exons 1-2 of PVT1. RNAseq analysis identified this chimeric gene as PVT1-ELK2AP. High-magnitude amplification of PVT1 gene was found on homogeneously staining region at the derivative chromosome 8 as detected by FISH with PVT1-S probe. The amplicon harbored both MYC and PVT1 gene, the size of which was 1.4Mb. The current study suggests that chimeric formation and amplification of lncRNA PVT1 gene may contribute to the pathophysiology and the molecular mechanism of refractoriness to treatment in diffuse large B-cell lymphoma.

Academic Significance and Societal Importance of the Research Achievements

非ホジキンリンパ腫の難治性に関与する新規分子異常が同定できれば，診断や適切な治療法選択の指標と応用できる．そのためには，PVT1キメラをゲノムやmRNAレベルで迅速に検出する臨床検査法の確立が重要であり，PCRやFISHによって日常診療への導入が促進される．さらに，新規分子異常が同定は新規治療薬の開発にも寄与する．新規分子異常に基づいた層別化あるいはリスク分類を確立し，適切な治療戦略が立案できれば，難治性であるがゆえの過剰治療を回避することが可能である．人口構成が高齢化するなか非ホジキンリンパ腫の罹患率は上昇しているため，本研究の社会的ならびに医療経済的なインパクトは大きいと考えられる．

Research Products

• [Journal Article] A novel method of amplified fluorescent in situ hybridization for detection of chromosomal microdeletions in B cell lymphoma. (2019)
  • Author(s): Mizuno Y, Chinen Y, Tsukamoto T, Takimoto-Shimomura T, Matsumura-Kimoto Y, Fujibayashi Y, Kuwahara-Ota S, Fujino T, Nishiyama D, Shimura Y, Kobayashi T, Horiike S, Taniwaki M, Kuroda J.
  • Journal Title: Int J Hematol. Volume: 109 Issue: 5 Pages: 593-602
  • DOI: 10.1007/s12185-019-02617-x
  • Peer Reviewed
• [Journal Article] Establishment and characterization of a novel vincristine-resistant diffuse large B-cell lymphoma cell line containing the 8q24 homogeneously staining region (2018)
  • Author(s): Mizuno S、Hanamura I、Ota Akinobu、Karnan S、Kanasugi J、Nakamura A、Takasugi S、Uchino Ki、Horio T、Goto、Murakami S、Gotou M、Yamamoto H、Watarai M、Shikami M、Hosokawa Y、Miwa H、Taniwaki M、Ueda R、Nitta M、Takami A
  • Journal Title: FEBS Open Bio Volume: 8 Issue: 12 Pages: 1977-1991
  • DOI: 10.1002/2211-5463.12538
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial. (2018)
  • Author(s): Watanabe T, Tobinai K, Wakabayashi M, Morishima Y, Kobayashi H, Kinoshita T, Suzuki T, Yamaguchi M, Ando K, Ogura M, Taniwaki M, Uike N, Yoshino T, Nawano S, Terauchi T, Hotta T, Nagai H, Tsukasaki K; JCOG0203 Collaborators（Yamauchi T et al.）.
  • Journal Title: Lancet Haematol Volume: 5 Issue: 11 Pages: 520-531
  • DOI: 10.1016/s2352-3026(18)30155-8
  • Peer Reviewed / Open Access
• [Journal Article] Dual targeting of bromodomain-containing 4 by AZD5153 and BCL2 by AZD4320 against B-cell lymphomas concomitantly overexpressing c-MYC and BCL2 (2018)
  • Author(s): Takimoto-Shimomura Tomoko、Tsukamoto Taku、Maegawa Saori、Fujibayashi Yuto、Matsumura-Kimoto Yayoi、Mizuno Yoshimi、Chinen Yoshiaki、Shimura Yuji、Mizutani Shinsuke、Horiike Shigeo、Taniwaki Masafumi、Kobayashi Tsutomu、Kuroda Junya
  • Journal Title: Investigational New Drugs Volume: 37 Issue: 2 Pages: 210-222
  • DOI: 10.1007/s10637-018-0623-8
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of obinutuzumab in patients with previously untreated follicular lymphoma: a subgroup analysis of patients enrolled in Japan in the randomized phase III GALLIUM trial. (2018)
  • Author(s): Ohmachi K, Tobinai K, Kinoshita T, Ishikawa T, Hatake K, Ichikawa S, Ohmine K, Kamitsuji Y, Choi I, Chou T, Tsukasaki K, Kumagai K, Taniwaki M, Uchida T, Kikukawa Y, Kubo K, Mihara K, Tsukamoto N, Izutsu K, Yoshida I, Ishida F, Usui N, Iida S, Murayama T, Ueda E, Kuriki H, Ando K
  • Journal Title: Int J Hematol. Volume: 108 Issue: 5 Pages: 499-509
  • DOI: 10.1007/s12185-018-2497-0
• [Journal Article] R-High-CHOP/CHASER/LEED with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma: JCOG0406 STUDY (2018)
  • Author(s): Ogura M, Yamamoto K, Morishima Y, Wakabayashi M, Tobinai K, Ando K, Uike N, Kurosawa M, Gomyo H, Taniwaki M, Nosaka K, Tsukamoto N, Shimoyama T, Fukuhara N, Yakushijin Y, Ohnishi K, Miyazaki K, et al.; Japan Clinical Oncology Group- Lymphoma Study Group (JCOG-LSG)
  • Journal Title: Cancer Sci. Volume: 109 Issue: 9 Pages: 2830-2840
  • DOI: 10.1111/cas.13719
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and Characteristics of a Novel Mantle Cell Lymphoma-derived Cell Line and a Bendamustine-resistant Subline (2018)
  • Author(s): Takimoto-Shimomura T, Nagoshi H, Maegawa S, Fujibayashi Y, Tsukamoto T, Matsumura-Kimoto Y, Mizuno Y, Chinen Y, Mizutani S, Shimura Y, Horiike S, Taniwaki M, Kobayashi T, Kuroda J
  • Journal Title: Cancer Genomics Proteomics Volume: 15 Pages: 213-223
  • Peer Reviewed / Open Access
• [Journal Article] Elotuzumab for the treatment of relapsed or refractory multiple myeloma, with special reference to its modes of action and SLAMF7 signaling. (2018)
  • Author(s): Taniwaki M, Yoshida M, Matsumoto Y, Shimura K, Kuroda J, Kaneko H.
  • Journal Title: Mediterr J Hematol Infect Dis. Volume: 10 Issue: 1 Pages: 1-16
  • DOI: 10.4084/mjhid.2018.014
  • Peer Reviewed / Open Access
• [Journal Article] Chromosomal abnormality variation detected by G-banding is associated with prognosis of diffuse large B-cell lymphoma treated by R-CHOP-based therapy. (2018)
  • Author(s): Mizuno Y, Tsukamoto T, Kawata E, Uoshima N, Uchiyama H, Yokota I, Maegawa S, Takimoto T, Tanba K, Matsumura-Kimoto Y, Kuwahara-Ota S, Fujibayashi Y, Yamamoto-Sugitani M, Chinen Y, Shimura Y, Horiike S, Taniwaki M, Kobayashi T, Kuroda J.
  • Journal Title: Cancer Med. Volume: 7 Issue: 3 Pages: 655-664
  • DOI: 10.1002/cam4.1342
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic impact of a past or synchronous second cancer in diffuse large B cell lymphoma. (2018)
  • Author(s): Tanba K, Chinen Y, Uchiyama H, Uoshima N, Shimura K, Fuchida S, Kiyota M, Nakao M, Shimura Y, Kobayashi T, Horiike S, Wada K, Shimazaki C, Kaneko H, Kobayashi Y, Taniwaki M, Kuroda J.
  • Journal Title: Blood Cancer J. Volume: 8 Issue: 1 Pages: 1-5
  • DOI: 10.1038/s41408-017-0043-6
  • Peer Reviewed / Open Access
• [Journal Article] Expression of Master Regulators of T-cell, Helper T-cell and Follicular Helper T-cell Differentiation in Angioimmunoblastic T-cell Lymphoma (2017)
  • Author(s): Matsumoto Y, Nagoshi H, Yoshida M, Kato S, Kuroda J, Shimura K, Kaneko H, Horiike S, Nakamura S, Taniwaki M.
  • Journal Title: Internal Medicine Volume: 56 Issue: 21 Pages: 2851-2856
  • DOI: 10.2169/internalmedicine.8570-16
  • NAID: 130006191969
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Hairy B-Cell lymphoproliferative disorder and its differential diagnosis: a case with long-term follow-up. (2017)
  • Author(s): Matsuda K, Matsumoto Y, Yoshida M, Shimura K, Kaneko H, Inaba T, Horiike S, Kuroda J, Taniwaki M.
  • Journal Title: Mediterr J Hematol Infect Dis. Volume: 9 Issue: 1 Pages: 1-5
  • DOI: 10.4084/mjhid.2017.054
  • Peer Reviewed / Open Access
• [Journal Article] Clinicopathological analysis of 46 cases with CD4+ and/or CD56+ immature haematolymphoid malignancy: reappraisal of blastic plasmacytoid dendritic cell and related neoplasms. (2017)
  • Author(s): Suzuki Y, Kato S, Kohno K, Satou A, Eladl AE, Asano N, Kono M, Kato Y, Taniwaki M, Akiyama M, Nakamura S.
  • Journal Title: Histopathology Volume: 71 Issue: 6 Pages: 972-984
  • DOI: 10.1111/his.13340
  • Peer Reviewed
• [Journal Article] Romidepsin in Japanese patients with relapsed or refractory peripheral T-cell lymphoma: a phase I/II and pharmacokinetics study. (2017)
  • Author(s): Maruyama D, Tobinai K, Ogura M, Uchida T, Hatake K, Taniwaki M, Ando K, Tsukasaki K, Ishida T, Kobayashi N, Ishizawa K, Tatsumi Y, Kato K, Kiguchi T, Ikezoe T, Laille E, Ro T, Tamakoshi H, Sakurai S, Ohtsu T.
  • Journal Title: Int J Hematol. Volume: 106 Issue: 5 Pages: 655-665
  • DOI: 10.1007/s12185-017-2286-1
  • Peer Reviewed
• [Journal Article] Molecular heterogeneity in APIP-FGFR2 fusion transcripts with diversity of genomic breakpoints in gastric cancer high-level amplifications at 11p13 and 10q26 (2017)
  • Author(s): Okuda T, Taki T, Nishida K Chinen Y, Nagoashi H, Sakakura C, Ohtsuji E, Taniwaki M
  • Journal Title: Oncol Lett Volume: 13 Issue: 1 Pages: 215-221
  • DOI: 10.3892/ol.2016.5386
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Detection of chromosomal abnormalities by G-banding and prognostic impact in follicular lymphoma in the rituximab era. (2017)
  • Author(s): Tsukamoto T, Kiyota M, Kawata E, Uoshima N, Tatekawa S, Chinen Y, Nagoshi H, Mizutani S, Shimura Y, Yamamoto-Sugitani M, Kobayashi T, Horiike S, Yasukawa S, Yanagisawa A, Taniwaki M, Kuroda J.
  • Journal Title: Int J Hematol. Volume: 105 Issue: 5 Pages: 658-667
  • DOI: 10.1007/s12185-016-2166-0
  • Peer Reviewed
• [Journal Article] A multicenter phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma. (2017)
  • Author(s): Maruyama D, Hatake K, Kinoshita T, Fukuhara N, Choi I, Taniwaki M, Ando K, Terui Y, Higuchi Y, Onishi Y, Abe Y, Kobayashi T, Shirasugi Y, Tobinai K.
  • Journal Title: Cancer Sci. Volume: － Issue: 5 Pages: 1007-1012
  • DOI: 10.1111/cas.13230
  • Peer Reviewed / Open Access
• [Journal Article] Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults (2016)
  • Author(s): 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 Taniwaki, et al.
  • Journal Title: Nature genetics Volume: in press Issue: 5 Pages: 409-417
  • DOI: 10.1038/ng.3535
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] B細胞リンパ腫細胞株から検出した新規キメラ遺伝子PVT1-ELK2AP (2018)
  • Author(s): 松本 洋典, 滝 智彦, 知念 良顕, 佐々木 奈々, 吉田 美穂子, 堤 康彦, 名越 久朗, 志村 和穂, 兼子 裕人, 堀池 重夫, 黒田 純也, 谷脇 雅史
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 増幅FISH法によるB細胞リンパ腫のCDKN2A微小欠損の検出 (2018)
  • Author(s): 水野 芳美, 知念 良顕, 塚本 拓, 下村 とも子, 志村 勇司, 古林 勉, 堀池 重夫, 谷脇 雅史, 黒田 純也
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] マントル細胞リンパ腫におけるBRD4標的遺伝子の解析 (2018)
  • Author(s): 塚本 拓, 中畑 新吾, 佐藤 隆一, 金井 昭教, 中野 正和, 稲葉 俊哉, 谷脇 雅史, 田代 啓, 森下 和広, 黒田 純也
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Genome-Wide Analysis of BRD4-Targets Reveals the Therapeutic Relevance of Simultaneous Targeting of BCR Pathway and Ikzf-Myc Axis in Mantle Cell Lymphoma (2018)
  • Author(s): Junya Kuroda, Taku Tsukamoto, Shingo Nakahata, Kazuhiro Morishita, Ryuichi Sato Akinori Kanai, Toshiya Inaba, Masakazu Nakano, Kei Tashiro and Masafumi Taniwaki
  • Organizer: 60th Annual Meeting and Exposition
• [Presentation] Updated report of a phase I/II multicenter study of forodesine, a purine nucleoside phosphorylase inhibitor, in Japanese patients with relapsed peripheral T-cell lymphoma. (2017)
  • Author(s): Shibayama H, Tobinai K, Tsukasaki K, Uchida T, Maeda Y, Nagai H, Kurosawa M, Abe Y, Hatake K, Ando K, Yoshida I, Hidaka M, Murayama T, Okitsu Y, Tsukamoto N, Taniwaki T, Suzumiya J, Tamura K, Yamauchi T, Ueda R.
  • Organizer: 59th The American Society of Hematology Annual Meeting and Exposition.
  • Int'l Joint Research
• [Presentation] Short-form of BCL11B contributes to tumorigenesis of adult T-cell leukiema/lymphoma. (2017)
  • Author(s): Nakahata S, Ichikawa T, Saito Y, Taki T, Tanwiaki M, Morishita K.
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Chromosomal abnormalities and prognostic impacts in follicular lymphoma in the era of Rituximab. (2017)
  • Author(s): Tsukamoto T, Kawata E, Uoshima N, Chinen Y, Shimura Y, Yamamoto-Sugitani M, Kobayashi T, Horiike S, Yasukawa S, Yanagisawa A, Taniwaki M, Kuroda J.
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] TCL-001: A phase I/II Japanese study of romidepsin in relapsed/refractory peripheral T-cell lymphoma. (2017)
  • Author(s): Taniwaki M, Maruyama D, Tobinai K, Ogura M, Hatake K, Uchida T, Ando K, Tsukasaki K, Ishida T, Kobayashi N, Ishizawa K, Tatsumi Y, Kato K, Kiguchi T, Ikezoe T, Laille E, Ro T, Tamakoshi H, Sakurai S, Ohtsu T.
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Serum albumin predicts outcome of intensive therapy for 80-year or older patients with DLBCL. (2017)
  • Author(s): Kaneko H, Shimura K, Yoshida M, Matsumoto Y, Taniwaki M, Yokota S, Horiike S, Kuroda J.
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Expression of master regulators of T-cell differentiation in adult T-cell leukemia/lymphoma. (2017)
  • Author(s): Matsumoto Y, Yoshida M, Shimura K, Kaneko H, Horiike S, Kuroda J, Taniwaki M.
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] More Somatic Mutations Including Those in the Aid-Motif with High-Risk, Histologically Non-Transformed Follicular Lymphomas. (2016)
  • Author(s): Tsukamoto T, Nakano M, Sato R, Adachi H, Kiyota M, Yasukawa S, Tatekawa S, Chinen Y, Nagoshi H, Mizutani S, Shimura Y, Yamamoto-Sugitani M, Kobayashi T, Taki T, Horiike S, Yanagisawa A, Taniwaki M, Tashiro K, Kuroda J.
  • Organizer: 58th The American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: San Diego. USA
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Comprehensive analysis of conjoined genes in DLBCL cell line, KPUM-UH1 by RNA-Seq. (2016)
  • Author(s): Matsumoto Y, Taki T, Chinen Y, Sato R, Adachi H, Mizutani S, Nagoshi H, Shimura Y, Yoshida M, Sugitani-Yamamoto M, Kobayashi T, Kuroda J, Shimura K, Nakano M, Horiike S, Ohkawara Y, Tashiro K, Taniwaki M.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] NDRG2 down-regulation induces hypoxic resistance via activation of PI3K/AKT signaling in ATLL. (2016)
  • Author(s): Nakahata S, Ichikawa T, Saito Y, Taki T, Taniwaki M, Morishita K.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] PDPK1 is the potential therapeutic target in mantle cell lymphoma. (2016)
  • Author(s): Maegawa S, Tatekawa S, Chinen Y, Tsukamoto T, Tanba K, Kimoto-Matsumura Y, Takimoto T, Mizuno Y, Sugitani-Yamamoto M, Taniwaki M, Kuroda J.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Karyotypic evolution in the prognostic indexes-defined high-risk diffuse large B cell lymphoma. (2016)
  • Author(s): Mizuno Y, Kobayashi T, Shimura Y, Tatekawa S, Tsukamoto T, Maegawa S, Tanba K, Kimoto-Matsumura Y, Takimoto T, Kuwahara S, Chinen Y, Nagoshi H, Sugitani-Yamamoto M, Horiike S, Taniwaki M, Kuroda J.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13