CRISPR screening for identification of molecular targets of T/NK cell lymphomas

• Project/Area Number: 18K08313
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Hokkaido University
• Principal Investigator: Nakagawa Masao 北海道大学, 医学研究院, 助教 (80435859)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: T細胞リンパ腫 / NK細胞リンパ腫 / ATLL / CRISPR / 分子標的治療 / T/NK細胞リンパ腫 / CRISPRスクリーニング / T細胞性リンパ腫 / NK細胞性リンパ腫

Outline of Final Research Achievements

In this study, we performed genome-wide CRISPR-Cas9 screens in multiple T/NK lymphoma cell lines for identifying essential genes for cellular proliferation/survival in a series of T/NK cell lymphoma cell lines. Positive and negative control sgRNAs were correctly identified through the entire screening, confirming the validity of the screening results. We identified genes which were selectively essential for each diease group in T/NK cell lymphomas. Some among the essential genes were confirmed in the follow-up functional experiments. All together, we established an entire list of candidate genes for molecular targeted therapies in T/NK cell lymphomas.

Academic Significance and Societal Importance of the Research Achievements

T/NK細胞リンパ腫の多くは現行の治療に対して５年生存率３０％と予後不良である。今回の研究からT/NK細胞リンパ腫の治療標的分子・分子シグナリングの包括的リストを作成できたことで、新規分子標的治療開発が加速され、将来的にT/NK細胞リンパ腫の治療成績の向上に貢献することができる。また、T/NK細胞リンパ腫の増殖・生存の分子メカニズムの理解が進んだ点は学術的意義が高い。

Research Products

• [Int'l Joint Research] National Cancer Institute, NIH/Fox Chase Cancer Center(米国)
• [Int'l Joint Research] Fox Chase Cancer Center/National Institutes of Health(米国)
• [Int'l Joint Research] Fox Chase Cancer Center/National Institutes of Health(米国)
• [Journal Article] A novel model of alternative NF-κB pathway activation in anaplastic large cell lymphoma (2020)
  • Author(s): Wang Hongbo、Wei Wei、Zhang Jing-Ping、Song Zhihui、Li Yangyang、Xiao Wenming、Liu Yijun、Zeng Mu-Sheng、Petrus Michael N.、Thomas Craig J.、Kadin Marshall E.、Nakagawa Masao、Waldmann Thomas A.、Yang Yibin
  • Journal Title: Leukemia Volume: － Issue: 7 Pages: 1976-1989
  • DOI: 10.1038/s41375-020-01088-y
• [Journal Article] A novel model of controlling PD-L1 expression in ALK+ Anaplastic Large Cell Lymphoma (2019)
  • Author(s): Zhang, JP., Song, Z., Wang, HB., Lang, L., Yang YZ., Xiao, W., Webster, DE., Wei, W., Barta, SK., Kadin, ME., Staudt, LM., Nakagawa, M., and Yang, Y.
  • Journal Title: Blood Volume: 132 Issue: 2 Pages: 171-185
  • DOI: 10.1182/blood.2019001043
  • Peer Reviewed
• [Journal Article] Ocular instillation of vitamin A-coupled liposomes containing HSP47 siRNA ameliorates dry eye syndrome in chronic GVHD. (2019)
  • Author(s): Ohigashi, H., Hashimoto, D., Hayase, E., Takahashi, S., Ara, T., Yamakawa, T., Sugita, J., Onozawa, M., Nakagawa, M., Teshima, T.
  • Journal Title: Blood Adv. Volume: 3 Issue: 7 Pages: 1003-1010
  • DOI: 10.1182/bloodadvances.2018028431
  • Peer Reviewed / Open Access
• [Journal Article] Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma (2018)
  • Author(s): Nakagawa M, Shaffer AL, Ceribelli M, Zhang M, Wright G, Huang DW, Xiao W, Powell J, Petrus MN, Yang Y, Phelan JD, Kohlhammer H, Dubois SP, Yoo HM, Bachy E, Webster DE, Yang Y,Xu W, Yu X, Zhao H, Bryant BR, Shimono J, Ishio T, Maeda M, Green PL, Waldmann TA , Staudt LM.
  • Journal Title: Cancer Cell Volume: 34 Issue: 2 Pages: 286-297.e10
  • DOI: 10.1016/j.ccell.2018.06.014
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The association between the incidence of intestinal graft-vs-host disease and antibiotic use after allogeneic hematopoietic stem cell transplantation (2018)
  • Author(s): Hidaka Daisuke、Hayase Eiko、Shiratori Souichi、Hasegawa Yuta、Ishio Takashi、Tateno Takahiro、Okada Kohei、Goto Hideki、Sugita Junichi、Onozawa Masahiro、Nakagawa Masao、Kahata Kaoru、Endo Tomoyuki、Hashimoto Daigo、Teshima Takanori
  • Journal Title: Clinical Transplantation Volume: 32 Issue: 9
  • DOI: 10.1111/ctr.13361
  • Peer Reviewed
• [Journal Article] A multiprotein supercomplex controlling oncogenic signalling in lymphoma (2018)
  • Author(s): Phelan JD, Young RM, Webster DE, Roulland S, Wright GW, Kasbekar M, Shaffer AL, Ceribelli M, Wang JQ, Schmitz R, Nakagawa M, Bachy E, Huang DW, Ji Y, Chen L, Yang Y, Zhao H, Yu X, Xu W, Palisoc MM et al.
  • Journal Title: Nature Volume: 560 Issue: 7718 Pages: 387-391
  • DOI: 10.1038/s41586-018-0290-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Development of a Fluorescence in Situ Hybridization Probe for Detecting IKZF1 Deletion Mutations in Patients with Acute Lymphoblastic Leukemia (2018)
  • Author(s): Hashiguchi Junichi、Onozawa Masahiro、Oguri Satoshi、Fujisawa Shinichi、Tsuji Masahisa、Okada Kohei、Nakagawa Masao、Hashimoto Daigo、Kahata Kaoru、Kondo Takeshi、Shimizu Chikara、Teshima Takanori
  • Journal Title: The Journal of Molecular Diagnostics Volume: 20 Issue: 4 Pages: 446-454
  • DOI: 10.1016/j.jmoldx.2018.02.005
  • NAID: 120006649182
  • Peer Reviewed
• [Journal Article] Hematogones Predict Better Outcome in Allogeneic Hematopoietic Stem Cell Transplantation Irrespective of Graft Sources (2018)
  • Author(s): Ishio Takashi、Sugita Junichi、Tateno Takahiro、Hidaka Daisuke、Hayase Eiko、Shiratori Souichi、Okada Kohei、Goto Hideki、Onozawa Masahiro、Nakagawa Masao、Hashimoto Daigo、Kahata Kaoru、Fujimoto Katsuya、Endo Tomoyuki、Kondo Takeshi、Teshima Takanori
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 24 Issue: 10 Pages: 1990-1996
  • DOI: 10.1016/j.bbmt.2018.06.011
  • Peer Reviewed
• [Journal Article] A novel heterozygous ITGB3 p.T720del inducing spontaneous activation of integrin αIIbβ3 in autosomal dominant macrothrombocytopenia with aggregation dysfunction (2018)
  • Author(s): Miyashita Naohiro、Onozawa Masahiro、Hayasaka Koji、Yamada Takahiro、Migita Ohsuke、Hata Kenichiro、Okada Kohei、Goto Hideki、Nakagawa Masao、Hashimoto Daigo、Kahata Kaoru、Kondo Takeshi、Kunishima Shinji、Teshima Takanori
  • Journal Title: Annals of Hematology Volume: 97 Issue: 4 Pages: 629-640
  • DOI: 10.1007/s00277-017-3214-4
  • NAID: 120006600942
  • Peer Reviewed
• [Presentation] Genome-wide CRISPR screen identifies CDK6 and mTORC1 as a combinatorial therapeutic target in ATLL (2020)
  • Author(s): Takashi Ishio, Sarvesh Kumar, Joji Shimono, Yuquan Lin, Emmanuel Bachy, Michael N. Petrus, Yandan Yang, Michiyuki Maeda, Hideki Goto, Satoshi Hashino, Takanori Teshima, Thomas A. Waldmann, Louis M. Staudt, Masao Nakagawa
  • Organizer: 日本血液学会総会
• [Presentation] Analysis of high-dose chemotherapy with autologous hematopoietic stem cell transplantation in PTCL (2020)
  • Author(s): 千葉雅尋、下埜城嗣、横田勲、重松明男、太田秀一、小林一、堤豊、山本聡、黒澤光俊、柿木康孝、近藤健、岩崎博、酒井基、宮城島拓人、長谷山美仁、永嶋貴博、國枝保幸、石尾崇、後藤秀樹、橋野聡、松野吉宏、中川雅夫、豊嶋崇徳
  • Organizer: 日本血液学会総会
• [Presentation] Genome-Wide Crispr Library Screening identifies genetic vulnerabilities and therapeutic targets in adult T-cell leukemia/lymphoma (2020)
  • Author(s): Takashi Ishio, Sarvesh Kumar, Joji Shimono, Yuquan Lin, Emmanuel Bachy, Michael N. Petrus, Yandan Yang, Michiyuki Maeda, Hideki Goto, Satoshi Hashino, Takanori Teshima, Thomas A. Waldmann, Louis M. Staudt, Masao Nakagawa
  • Organizer: 25th EHA Virtual
  • Int'l Joint Research
• [Presentation] The combination of the CDK4/6 inhibitor palbociclib with mTOR inhibitors showed addivity in the treatment of HTLV-1 associated adult T-cell leukemia (2020)
  • Author(s): Takashi Ishio, Sarvesh Kumar, Thomas A. Waldmann and Masao Nakagawa
  • Organizer: the 12th Annual T-cell Lymphoma Forum
  • Int'l Joint Research
• [Presentation] Genome-Wide CRISPR Library Screening Identifies CDK6 As Genetic Vulnerability in Adult T-Cell Leukemia/Lymphoma. (2019)
  • Author(s): Takashi Ishio, Joji Shimono, Sarvesh Kumar, Yuquan Lin, Emmanuel Bachy, Michael N. Petrus, Yandan Yang, Michiyuki Maeda, Hideki Goto, Hashino Satoshi, Takanori Teshima, Thomas A. Waldmann, Louis M. Staudt, and Masao Nakagawa
  • Organizer: 61st ASH Annual Meeting
  • Int'l Joint Research
• [Presentation] BATF3/IRF4 transcriptional complex suppresses cellular immunity-associated gene signature in HTLVI-associated ATLL cells (2019)
  • Author(s): Masao Nakagawa, Joji Shimono, Takashi Ishio, Takanori Teshima
  • Organizer: The 78th Annual Meeting of the Japanese Cancer Association
• [Presentation] Clinicopathological analysis of BATF3 and IRF4 in PTCL (2019)
  • Author(s): 下埜 城嗣、石尾崇、後藤秀樹、堤豊、盛暁生、小林一、黒澤光俊、柿木康孝、重松明男、太田秀一、酒井基、宮城島拓人、長谷山美仁、岩﨑博、山本聡、國枝 保幸、橋野聡、三好寛明、大島孝一、畑中 豊、松野吉宏、中川雅夫、豊嶋崇徳
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] "Targeting the HTLV-I-regulated BATF3/IRF4 Transcriptional Network in Adult T-Cell Leukemia/Lymphoma" (2019)
  • Author(s): Nakagawa M.
  • Organizer: "The 34th Nagoya International Cancer Treatment Symposium"
  • Int'l Joint Research / Invited
• [Presentation] Molecular mechanisms of HBZ for ATLL cell proliferation (2018)
  • Author(s): Nakagawa M, Endo T, Teshima T, Waldmann TA, Staudt LM
  • Organizer: The 28th annual Meeting of the Japanese Association for Antiviral Therapy
• [Presentation] Critical roles of BATF3/IRF4 in PTCL pathogenesis (2018)
  • Author(s): Nakagawa M.
  • Organizer: The 58th Annual Meeting of the Japanese Society for Lymphoreticular Tissue Research.
  • Invited
• [Presentation] Recent advances of molecular pathogenesis of B-cell lymphomas (2018)
  • Author(s): Nakagawa M.
  • Organizer: The 77th Annual Meeting of the Japanese Cancer Association
  • Int'l Joint Research
• [Presentation] PTCL におけるBATF3/IRF4 (2018)
  • Author(s): Nakagawa M.
  • Organizer: 第4 回リンパ腫分子病態研究会 沖縄シンポジウム
  • Invited
• [Remarks] 北海道大学大学院医学研究院 血液内科学教室 リンパ系腫瘍グループ
  • URL: http://www.hokudai-hematology.jp/medical/basic-research/index3.html
• [Remarks] 北海道大学大学院 医学研究院 血液内科 リンパ系腫瘍研究グループ
  • URL: http://www.hokudai-hematology.jp/medical/basic-research/index3.html