Development of a novel therapeutic strategy targeting MYC for leukemia with monosomy 7

• Project/Area Number: 21K16241
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Matsuda Kensuke 東京大学, 医学部附属病院, 助教 (40880175)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2021: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: モノソミー7 / 合成致死 / MYC / エピゲノム / BRD4

Outline of Research at the Start

7番染色体のモノソミー（モノソミー7）を伴う白血病は化学療法に抵抗性で予後不良であり、分子病態に基づいた特異的な治療法の開発が切望されている。我々は、ヒストン修飾遺伝子を対象とした独自のスクリーニングを行い、モノソミー7白血病の生存に必須である遺伝子を複数同定した。興味深いことに、これら遺伝子はいずれもMYCを標的遺伝子としていることが一連の解析から明らかとなった。これらの知見に基づいて、本研究ではMYC遺伝子に着目したモノソミー7に対する新しい治療戦略の開発・応用を目指す。

Outline of Final Research Achievements

The aim of this study is to develop MYC-targeted therapies for leukemias with monosomy of chromosome 7 (monosomy 7). Our group identified several target genes in a therapeutic target screen based on the concept of synthetic lethality, suggesting that they may exert their effects by downregulating MYC. Using leukemia cell lines and patient samples, we confirmed that MYC inhibitory therapy inhibited the growth of monosomy 7 leukemia cells. In addition, we found that MYC inhibition contribute to a lower tumor progression and mouse survival in an immunodeficient mouse model. MYC is required for survival. MYC is an essential gene for cell function, but its expression level was suppressed to a lower level in monosomy 7 leukemia, which may induce the vulnerability to MYC inhibitory therapy.

Academic Significance and Societal Importance of the Research Achievements

本研究では、難治性であるモノソミー7を伴う白血病の新しい脆弱性を明らかにした。加えて、本研究は、染色体欠失という事象に対して、新しい治療標的探索アプローチを提示する可能性がある。本研究が発展し、難治性白血病に対する新しい治療法の開発及び治療成績向上が期待される。

Research Products

• [Journal Article] Prompt Initiation of Conventional Chemotherapy to Avoid Early Death in Patients with Newly Diagnosed Acute Promyelocytic Leukemia (2023)
  • Author(s): Matsuda Kensuke、Oyama Takashi、Maki Hiroaki、Nakazaki Kumi、Yasunaga Megumi、Honda Akira、Masamoto Yosuke、Kurokawa Mineo
  • Journal Title: Internal Medicine Volume: 62 Issue: 15 Pages: 2181-2185
  • DOI: 10.2169/internalmedicine.0937-22
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2023-08-01
  • Peer Reviewed
• [Journal Article] Expansion of large granular lymphocytes after autologous hematopoietic stem cell transplantation (2023)
  • Author(s): Yoshida Mina、Matsuda Kensuke、Taoka Kazuki、Honda Akira、Maki Hiroaki、Masamoto Yosuke、Jona Masahiro、Nishikawa Masako、Yatomi Yutaka、Kurokawa Mineo
  • Journal Title: International Journal of Hematology Volume: Online ahead of print Issue: 6 Pages: 839-844
  • DOI: 10.1007/s12185-023-03540-y
  • Peer Reviewed
• [Journal Article] High susceptibility of febrile neutropenia in Japanese patients receiving venetoclax plus azacitidine therapy for acute myeloid leukemia (2023)
  • Author(s): Matsuda Kensuke、Yoshida Takashi、Sugimoto Koichi
  • Journal Title: Annals of Hematology Volume: 102 Issue: 4 Pages: 971-972
  • DOI: 10.1007/s00277-023-05143-3
  • Peer Reviewed
• [Journal Article] Toxic shock like syndrome caused by Streptococcus agalactiae bacteremia during treatment for multiple myeloma (2023)
  • Author(s): Yoshida Mina、Matsuda Kensuke、Endo Kiyora、Honda Akira、Maki Hiroaki、Taoka Kazuki、Masamoto Yosuke、Wakimoto Yuji、Jubishi Daisuke、Moriya Kyoji、Kurokawa Mineo
  • Journal Title: Journal of Infection and Chemotherapy Volume: 29 Issue: 4 Pages: 407-409
  • DOI: 10.1016/j.jiac.2022.12.001
  • Peer Reviewed
• [Journal Article] Comparison of transplant outcomes between haploidentical transplantation and single cord blood transplantation in non‐remission acute myeloid leukaemia: A nationwide retrospective study (2023)
  • Author(s): K Matsuda , T Konuma , K Fuse , M Masuko , K Kawamura , M Hirayama , N Uchida , K Ikegame , A Wake , T Eto , N Doki , S Miyakoshi , M Tanaka , S Takahashi , M Onizuka , K Kato , T Kimura , T Ichinohe , N Takayama , H Kobayashi , H Nakamae , Y Atsuta , J Kanda , M Yanada
  • Journal Title: British Journal of Haematology Volume: 201 Issue: 1 Pages: 106-113
  • DOI: 10.1111/bjh.18530
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Graft-versus-Host Disease on Post-Transplantation Outcomes following Single Cord Blood Transplantation Compared with Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for Adult Acute Myeloid Leukemia (2023)
  • Author(s): Konuma Takaaki、Matsuda Kensuke、Shimomura Yoshimitsu、et al.
  • Journal Title: Transplantation and Cellular Therapy Volume: Online ahead of print Issue: 6 Pages: 365.e1-365.e11
  • DOI: 10.1016/j.jtct.2023.03.001
  • Peer Reviewed
• [Journal Article] Autologous stem cell transplantation after pola-BR regimen as a salvage therapy in relapsed diffuse large B-cell lymphoma (2023)
  • Author(s): 松田 健佑、藤岡 洋成、奥田 慎也、杉本 耕一
  • Journal Title: Rinsho Ketsueki Volume: 64 Issue: 3 Pages: 214-217
  • DOI: 10.11406/rinketsu.64.214
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Bing-Neel Syndrome Successfully Treated with Tirabrutinib (2022)
  • Author(s): Oyama Takashi、Taoka Kazuki、Chiba Akira、Matsuda Kensuke、Maki Hiroaki、Masamoto Yosuke、Kurokawa Mineo
  • Journal Title: Internal Medicine Volume: 61 Issue: 23 Pages: 3575-3579
  • DOI: 10.2169/internalmedicine.9545-22
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2022-12-01
  • Peer Reviewed
• [Journal Article] Institutional factors associated with early mortality of newly diagnosed acute promyelocytic leukemia (2022)
  • Author(s): Matsuda Kensuke、Jo Taisuke、Matsui Hiroki、Fushimi Kiyohide、Yasunaga Hideo、Sugimoto Koichi
  • Journal Title: Blood Cancer Journal Volume: 12 Issue: 12 Pages: 167-167
  • DOI: 10.1038/s41408-022-00767-6
  • Peer Reviewed
• [Journal Article] Cerebral toxoplasmosis complicating lymphoplasmacytic lymphoma in partial remission (2022)
  • Author(s): Murakami Daisuke、Maki Hiroaki、Matsuda Kensuke、Masamoto Yosuke、Suzuki Fumio、Amemiya Shiori、Osawa Kazuhiro、Hinata Munetoshi、Ikemura Masako、Ushiku Tetsuo、Kurokawa Mineo
  • Journal Title: Journal of Infection and Chemotherapy Volume: 28 Issue: 2 Pages: 279-282
  • DOI: 10.1016/j.jiac.2021.09.005
  • Peer Reviewed
• [Journal Article] Allogeneic Hematopoietic Cell Transplantation for Patients with Relapsed Acute Promyelocytic Leukemia (2022)
  • Author(s): Yanada Masamitsu、Matsuda Kensuke、Ishii Hiroto、Fukuda Takahiro、Ozeki Kazutaka、Ota Shuichi、Tashiro Haruko、Uchida Naoyuki、Kako Shinichi、Doki Noriko、Kawakita Toshiro、Onishi Yasushi、Takada Satoru、Kondo Yukio、Tanaka Junji、Kanda Yoshinobu、Atsuta Yoshiko、Yano Shingo
  • Journal Title: Transplantation and Cellular Therapy Volume: 28 Issue: 12 Pages: 847.e1-847.e8
  • DOI: 10.1016/j.jtct.2022.09.021
  • Peer Reviewed
• [Journal Article] Severe infections and renal dysfunction during immunosuppressive therapy with cyclosporine A for aplastic anemia (2022)
  • Author(s): Murakami Daisuke、Matsuda Kensuke、Honda Akira、Masamoto Yosuke、Kurokawa Mineo
  • Journal Title: International Journal of Hematology Volume: 116 Issue: 4 Pages: 482-488
  • DOI: 10.1007/s12185-022-03399-5
  • Peer Reviewed
• [Journal Article] Risk of febrile neutropenia in very elderly patients aged ≥80 years receiving their first cycle of R‐CHOP regimen: a nationwide real‐world study in Japan (2022)
  • Author(s): Matsuda Kensuke、Jo Taisuke、Shimura Arika、Honda Akira、Taoka Kazuki、Masamoto Yosuke、Matsui Hiroki、Fushimi Kiyohide、Yasunaga Hideo、Kurokawa Mineo
  • Journal Title: British Journal of Haematology Volume: 197 Issue: 3
  • DOI: 10.1111/bjh.18028
  • Peer Reviewed
• [Journal Article] Long-term follow-up of central nervous system relapse in patients with acute promyelocytic leukemia treated with all-<i>trans</i> retinoic acid and chemotherapy (2022)
  • Author(s): Oyama Takashi、Matsuda Kensuke、Honda Akira、Yasunaga Megumi、Nakazaki Kumi、Maki Hiroaki、Masamoto Yosuke、Kurokawa Mineo
  • Journal Title: Leukemia & Lymphoma Volume: 63 Issue: 14 Pages: 3497-3500
  • DOI: 10.1080/10428194.2022.2131421
  • Peer Reviewed
• [Journal Article] Cord blood versus haploidentical transplantations for non‐remission acute myeloid leukaemia: Authors' reply (2022)
  • Author(s): Matsuda Kensuke、Konuma Takaaki、Yanada Masamitsu
  • Journal Title: British Journal of Haematology Volume: 200 Issue: 5 Pages: 678-679
  • DOI: 10.1111/bjh.18626
  • Peer Reviewed
• [Journal Article] Clinical characteristics of steroid-responsive but dependent chronic graft-versus-host disease: a multicenter retrospective analysis (2022)
  • Author(s): Oyama Takashi、Matsuda Kensuke、Honda Akira、Maki Hiroaki、Masamoto Yosuke、Murakami Daisuke、Toya Takashi、Sakurai Masatoshi、Kataoka Keisuke、Doki Noriko、Kurokawa Mineo
  • Journal Title: International Journal of Hematology Volume: 117 Issue: 2 Pages: 260-268
  • DOI: 10.1007/s12185-022-03471-0
  • Peer Reviewed
• [Presentation] 急性骨髄性白血病非寛解期における臍帯血移植とハプロ移植の比較 (2022)
  • Author(s): 松田健佑、小沼 貴晶、布施 香子、増子 正義、河村 浩二、平山 雅浩、内田 直之、池亀 和博、和氣 敦、衛藤 徹也、土岐 典子、宮腰 重三郎、田中 正嗣、高橋 聡、鬼塚 真仁、加藤 光次、木村 貴文、一戸 辰夫、熱田 由子、諫田 淳也、柳田 正光
  • Organizer: 第44回日本造血・免疫細胞療法学会総会
• [Presentation] 血液領域における日米間のドラッグラグの疾患別解析 (2022)
  • Author(s): 松田健佑、永井純正、杉本耕一
  • Organizer: 第81回日本癌学会総会
• [Presentation] 早期死亡を防ぐための未治療急性前骨髄球性白血病のマネジメントに関する後方視的解析 (2022)
  • Author(s): 松田健佑, 大山貴司、牧宏彰、中崎久美、安永愛、本田晃, 正本庸介, 黒川峰夫
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Association between Hospital Volume and Early Mortality of Newly Diagnosed Acute Promyelocytic Leukemia: A Nationwide Database Study in Japan (2022)
  • Author(s): Kensuke Matsuda, Taisuke Jo, Hideo Yasunaga, Koichi Sugimoto
  • Organizer: 64th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Disease-Specific Analysis of Drug Approval Delay in Hematologic Malignancies between Japan and the U.S. and between Europe and the U.S. (2022)
  • Author(s): Kensuke Matsuda, Sumimasa Nagai, Koichi Sugimoto
  • Organizer: 64th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Book] 臨床血液 (2023)
  • Author(s): 松田健佑
  • Total Pages: 1
  • Publisher: J-Stage
• [Book] 血液内科 (2022)
  • Author(s): 松田健佑、牧宏彰、黒川峰夫
  • Total Pages: 5
  • Publisher: 科学評論社