Prediction of the onset of treatment-related myeloproliferative neoplasms after treatment for malignant lymphoma by genetic analysis of bone marrow cell

• Project/Area Number: 19K16811
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Katagiri Seiichiro 東京医科大学, 医学部, 助教 (50532298)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 悪性リンパ腫 / 治療関連骨髄腫瘍 / クローン性造血 / 治療関連骨髄性腫瘍 / targeted deep sequencing / Targeted deep sequencing / CHIP / t-MN

Outline of Research at the Start

治療関連骨髄性腫瘍 ( t-MN)は化学療法や放射線治療後を行った患者において予後に直結する重要な合併症である。骨髄異形成症候群の疾患背景としてクローン性造血の存在が注目されている。さらにt-MNにおいても一次腫瘍に対する化学療法前の末梢血検体で、t-MN発症に関連する変異が検出されている。本研究では次世代シークエンス技術を用いて、悪性リンパ腫診断時の骨髄におけるクローン性造血を解析することで、t-MN発症の潜在的リスクを予測する。悪性リンパ腫診断時で治療後t-MNのリスクを予測することにより、個々の患者に合った治療戦略を検討できるようになることが期待される。

Outline of Final Research Achievements

In this study, we used next-generation sequencing technology to perform targeted deep sequencing only at specific sites and analyze clonal hematopoies in the bone marrow at the time of diagnosis of malignant lymphoma. The purpose was to predict the potential risk of developing therapy-related myeloid neoplasm (t-MN). For patients who developed t-MN after treatment for malignant lymphoma, we conducted a molecular analysis using myeloid targeted deep sequencing in pre-treatment and tMN BM samples. 80% of tMN patients showed clonal hematopoiesis in the BM before chemotherapy for ML. Furthermore, none of the major clones of clonal hematopoies found at the onset of malignant lymphoma had a common clone with t-MN that developed thereafter. From this result, it was considered that the existence of clonal hematopoies before chemotherapy may indicate the possibility of clonal instability that facilitates the emergence of new clones by chemotherapy.

Academic Significance and Societal Importance of the Research Achievements

悪性リンパ腫は治療関連骨髄性腫瘍の一次腫瘍として大きな割合を占めている。これまで悪性リンパ腫診断時の骨髄検体を用いて、t-MN発症を予測した研究は報告されておらず、本研究は悪性リンパ腫診断時の骨髄検体を用いてクローン性造血を評価することで、治療後のt-MN発症リスクの評価ができる可能性を示した。将来的に悪性リンパ腫治療後の二次発癌の可能性まで考慮した治療戦略が作られてることが期待される。

Research Products

• [Journal Article] Elevation of HHV-6 viral load mimicking HHV-6 reactivation after second umbilical cord blood transplantation in chromosomally integrated human herpesvirus-6 (2021)
  • Author(s): Katagiri Seiichiro、Akahane Daigo、Inukai Tatsuya、Otsuki Shunsuke、Yamada Arisa、Moriyama Mitsuru、Yamada Akiko、Asano Michiyo、Yoshizawa Seiichiro、Tanaka Yuko、Furuya Nahoko、Fujimoto Hiroaki、Gotoh Moritaka、Nakamura Shigeki、Gotoh Akihiko
  • Journal Title: Journal of Infection and Chemotherapy Volume: 27 Issue: 10 Pages: 1517-1519
  • DOI: 10.1016/j.jiac.2021.05.016
  • Peer Reviewed / Open Access
• [Journal Article] Relevance of diffusion-weighted imaging with background body signal suppression for staging, prognosis, morphology, treatment response, and apparent diffusion coefficient in plasma-cell neoplasms: A single-center, retrospective study (2021)
  • Author(s): Yamada Akiko、Araki Yoichi、Tanaka Yuko、Otsuki Shunsuke、Yamada Arisa、Moriyama Mitsuru、Katagiri Seiichiro、Suguro Tamiko、Asano Michiyo、Yoshizawa Seiichiro、Akahane Daigo、Furuya Nahoko、Fujimoto Hiroaki、Okabe Seiichi、Gotoh Moritaka、Suzuki Kunihito、Saito Kazuhiro、Gotoh Akihiko
  • Journal Title: PLOS ONE Volume: 16 Issue: 7 Pages: e0253025-e0253025
  • DOI: 10.1371/journal.pone.0253025
  • Peer Reviewed / Open Access
• [Journal Article] Cholecystectomy in a patient with paroxysmal nocturnal haemoglobinuria undergoing ravulizumab maintenance treatment (2021)
  • Author(s): Moriyama Mitsuru、Aota Yasuo、Okabe Masahiro、Osaka Yoshiaki、Katagiri Seiichiro、Akahane Daigo、Gotoh Akihiko
  • Journal Title: eJHaem Volume: 3 Issue: 1 Pages: 203-206
  • DOI: 10.1002/jha2.336
  • Peer Reviewed / Open Access
• [Journal Article] Epstein-Barr virus-associated post-transplant lymphoproliferative disease during dasatinib treatment occurred 10 years after umbilical cord blood transplantation (2021)
  • Author(s): Yamada Akiko、Katagiri Seiichiro、Moriyama Mitsuru、Asano Michiyo、Suguro Tamiko、Yoshizawa Seiichiro、Akahane Daigo、Tanaka Yuko、Furuya Nahoko、Fujimoto Hiroaki、Gotoh Moritaka、Aota Yasuo、Nakamura Naoya、Gotoh Akihiko
  • Journal Title: Journal of Infection and Chemotherapy Volume: － Issue: 7 Pages: 1076-1079
  • DOI: 10.1016/j.jiac.2021.01.009
  • Peer Reviewed
• [Journal Article] Overexpression of RUNX3 Represses RUNX1 to Drive Transformation of Myelodysplastic Syndrome (2020)
  • Author(s): Yokomizo-Nakano Takako、Kubota Sho、Bai Jie、Hamashima Ai、Morii Mariko、Sun Yuqi、Katagiri Seiichiro、Iimori Mihoko、Kanai Akinori、Tanaka Daiki、Oshima Motohiko、Harada Yuka、Ohyashiki Kazuma、Iwama Atsushi、Harada Hironori、Osato Motomi、Sashida Goro
  • Journal Title: Cancer Research Volume: 80 Issue: 12 Pages: 2523-2536
  • DOI: 10.1158/0008-5472.can-19-3167
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Successful cord blood transplantation for myelodysplastic syndrome complicated by Mycobacterium kansasii pneumonia (2020)
  • Author(s): Yamada Arisa、Akahane Daigo、Katagiri Seiichiro、Yoshizawa Seiichiro、Furuya Nahoko、Fujimoto Hiroaki、Gotoh Moritaka、Gotoh Akihiko
  • Journal Title: Transplant Infectious Disease Volume: － Issue: 4
  • DOI: 10.1111/tid.13463
  • Peer Reviewed
• [Journal Article] Downregulation of extracellular vesicle microRNA-101 derived from bone marrow mesenchymal stromal cells in myelodysplastic syndrome with disease progression. (2020)
  • Author(s): Saitoh Y, Umezu T, Imanishi S, Asano M, Yoshizawa S, Katagiri S, Suguro T, Fujimoto H, Akahane D, Kobayashi-Kawana C, Ohyashiki JH, Ohyashiki K.
  • Journal Title: Oncol Lett. Volume: 19(3) Pages: 2053-2061
  • DOI: 10.3892/ol.2020.11282
  • Peer Reviewed / Open Access
• [Journal Article] Successful treatment with gilteritinib for initially FMS‐like tyrosine kinase 3 gene internal tandem duplications‐positive elderly refractory acute myeloid leukemia that changed into FMS‐like tyrosine kinase 3 gene tyrosine kinase domain‐positive after cord blood transplantation (2019)
  • Author(s): Akahane Daigo、Moriyama Mitsuru、Yoshizawa Seiichiro、Katagiri Seiichiro、Fujimoto Hiroaki、Gotoh Akihiko
  • Journal Title: Geriatrics & Gerontology International Volume: 19 Issue: 10 Pages: 1063-1064
  • DOI: 10.1111/ggi.13772
  • Peer Reviewed
• [Journal Article] Predisposed genomic instability in pre-treatment bone marrow evolves to therapy-related myeloid neoplasms in malignant lymphoma. (2019)
  • Author(s): Katagiri S, Makishima H, Azuma K, Nannya Y, Saitoh Y, Yoshizawa S, Akahane D, Fujimoto H, Ito Y, Velaga R, Umezu T, Ohyashiki JH, Ogawa S, Ohyashiki K.
  • Journal Title: Haematologica. Volume: Nov 7 Issue: 7 Pages: 229856-229856
  • DOI: 10.3324/haematol.2019.229856
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Very late relapse with rapid BCR‐ABL1 elevation after more than seven years of treatment‐free remission with undetectable molecular residual disease in chronic myeloid leukaemia (2019)
  • Author(s): Katagiri Seiichiro、Gotoh Akihiko、Ohyashiki Kazuma
  • Journal Title: British Journal of Haematology Volume: 188 Issue: 2 Pages: 332-334
  • DOI: 10.1111/bjh.16285
  • Peer Reviewed / Open Access
• [Presentation] Genomic analysis of relapsed AML with RUNX1-RUNX1T1 in a comprehensive NGS multicenter study of AML (2021)
  • Author(s): 片桐誠一朗, 赤羽大悟, 後藤明彦, 池成基, 福島健太郎, 柴山浩彦, 細野奈穂子, 山内高弘, 江口基紀, 森下喬允, 小笠原励起, 近藤健, 柳田正光, 山本一仁, 古林勉, 黒田純也, 臼杵憲祐, 宇津欣和, 青墳信之, 吉満誠, 石塚賢治, 小野孝明, 高橋直人, 井山諭, 中村真, 中邑幸伸, 伊豆津宏二, 山内寛彦, 湯田淳一朗, 南陽介
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Genomic Analysis Focusing on RUNX1- RUNX1T1 in Japanese Patients with AML: HM- Screen-Japan 01 (2021)
  • Author(s): 片桐誠一朗, 赤羽大悟, 後藤明彦, 池成基, 福島健太郎, 柴山浩彦, 細野奈穂子, 山内高弘, 江口基紀, 森下喬允, 小笠原励起, 近藤健, 柳田正光, 山本一仁, 古林勉, 黒田純也, 臼杵憲祐, 宇津欣和, 青墳信之, 吉満誠, 石塚賢治, 小野孝明, 高橋直人, 井山諭, 中村真, 中邑幸伸, 伊豆津宏二, 山内寛彦, 湯田淳一朗, 南陽介
  • Organizer: 第63回アメリカ血液学会学術集会
  • Int'l Joint Research
• [Presentation] Blinatumomabにより白血病治療と感染症治療の両立が可能であったB細胞性リンパ芽球性白血病 (2021)
  • Author(s): 片桐誠一朗, 赤羽大悟, 大月俊輔, 山田ありさ, 森山充, 山田晃子, 勝呂多光子, 浅野倫代, 吉澤成一郎, 田中裕子, 古屋奈穂子, 藤本博昭, 岡部聖一, 後藤守孝, 伊藤良和, 後藤明彦
  • Organizer: 第14回 日本血液学会関東甲信越地方会
• [Presentation] 単施設における60歳以上の造血器腫瘍患者に対する同種造血幹細胞移植経験 (2020)
  • Author(s): 片桐誠一朗, 後藤守孝, 赤羽大悟, 大月俊輔, 山田ありさ, 森山充, 山田晃子, 勝呂多光子, 浅野倫代, 吉澤成一郎, 田中裕子, 古屋奈穂子, 藤本博昭, 岡部聖一, 伊藤良和, 後藤明彦
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] ALK-positive ALCL with TP53 deletion that resisted high-intensity treatment including allo-SCT (2019)
  • Author(s): Seiichiro Katagiri, Daigo Akahane, Tamiko Suguro, Michiyo Asano, Yuko Tanaka, Nahoko Furuya, Hiroaki Fujimoto, Naoya Nakamura, and Kazuma Ohyashiki
  • Organizer: 第81回日本血液学会学術集会