The role of tumor microenvironment in aggressive NK-cell leukemia

• Project/Area Number: 20J14747
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Jichi Medical University
• Principal Investigator: 亀田 和明 自治医科大学, 医学研究科, 特別研究員(DC2)
• Project Period (FY): 2020-04-24 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,100,000 (Direct Cost: ¥2,100,000); Fiscal Year 2021: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2020: ¥1,100,000 (Direct Cost: ¥1,100,000)
• Keywords: アグレッシブNK細胞白血病 / 異種移植マウスモデル / 肝臓 / 類洞 / CRISPR-Cas9

Outline of Research at the Start

アグレッシブNK細胞白血病（ANKL）という難治性血液がんの病態解明を目指す。この疾患は日本を含む東アジアが主な発症地域であり、本邦から新たな研究成果を出していく必要がある。がん細胞が体の中で増えていくには、がん自身だけではなく周囲の正常な組織の関与も重要な役割を果たす。本研究では、ANKLがどのような生体内環境の中で、どのようなサポートを受けて進むのかを様々な角度から研究して、新たな治療法の開発に結びつけることを目指す。

Outline of Annual Research Achievements

アグレッシブNK細胞白血病(ANKL)という難治性血液がんの病態解明を目指して研究を行った。まれな病気であり、患者さんの検体だけでは詳細な解析を行うことが困難である。そのため、白血病モデルマウスの作成を試み、成功した。年間で数百万人に一人しか発症しないというまれな病気であるにもかかわらず、患者さんから細胞をいただくことで4系統のモデルを作成することができた。作成したモデルを解析することで、この病気が今までは骨髄で増えると考えられていたのが、実は主に肝臓の類洞という部位で増殖するということを発見した。
今年度は、前年度の解析で得られた病態に関与する候補分子が、実際に白血病の生存・増殖に関わっているのかを検証した。具体的には、前年度に確立したマウス体内で実施できるCRISPR-Cas9システムを用いて、白血病細胞の受容体機能を喪失させたところ、白血病細胞の生存・増殖能力が低下してマウスの生存を延長させることを見出した。またその受容体のリガンドを白血病細胞に投与することで、Myc関連経路が亢進することが分かった。また、それ以外にも白血病細胞にとって重要な複数の受容体を見出した。そのうちの一つについては、阻害抗体を入手して白血病モデルマウスへ投与することで、治療効果が得られることがわかった。患者さんでもこの抗体で治療効果が得られるのかを検証するために、臨床試験を計画しているところである。
また複数の医療機関の協力を得て、ANKL患者さんの肝臓病理標本を入手した。そして患者さんの検体でも、腫瘍細胞が肝臓類洞に存在していることを確認できた。
これらの研究成果の一部は日本血液学会や米国血液学会で報告した。

Research Progress Status

令和3年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和3年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Persistent Expression of Recipient-type ABH Antigen after ABO-incompatible Allogeneic Hematopoietic Stem Cell Transplantation (2022)
  • Author(s): Misaki Yukiko、Kako Shinichi、Kawamura Shunto、Takeshita Junko、Yoshino Nozomu、Yoshimura Kazuki、Gomyo Ayumi、Akahoshi Yu、Tamaki Masaharu、Kusuda Machiko、Kameda Kazuaki、Wada Hidenori、Kawamura Koji、Sato Miki、Terasako-Saito Kiriko、Kimura Shun-ichi、Nakasone Hideki、Kishino Koji、Muroi Kazuo、Kanda Yoshinobu
  • Journal Title: Internal Medicine Volume: 61 Issue: 12 Pages: 1887-1890
  • DOI: 10.2169/internalmedicine.8315-21
  • NAID: 130008119254
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2022-06-15
  • Peer Reviewed
• [Journal Article] Autologous or allogeneic hematopoietic cell transplantation for relapsed or refractory PTCL-NOS or AITL (2022)
  • Author(s): Kameda Kazuaki、Kako Shinichi、Kim Sung-Won、et al.
  • Journal Title: Leukemia Volume: 36 Issue: 5 Pages: 1361-1370
  • DOI: 10.1038/s41375-022-01545-w
  • Peer Reviewed
• [Journal Article] Deletion of Y chromosome before allogeneic hematopoietic stem cell transplantation in male recipients with female donors (2022)
  • Author(s): Tamaki Masaharu、Kameda Kazuaki、Kimura Shun-ichi、Harada Naonori、Uchida Naoyuki、Doki Noriko、Tanaka Masatsugu、Ikegame Kazuhiro、Sawa Masashi、Katayama Yuta、Miyakoshi Shigesaburo、Ara Takahide、Kanda Junya、Onizuka Makoto、Fukuda Takahiro、Atsuta Yoshiko、Kanda Yoshinobu、Yakushijin Kimikazu、Nakasone Hideki
  • Journal Title: Blood Advances Volume: 6 Issue: 6 Pages: 1895-1903
  • DOI: 10.1182/bloodadvances.2021006456
  • Peer Reviewed / Open Access
• [Journal Article] Risk and Predictive Factors for Candidemia After Allogeneic Hematopoietic Cell Transplantation: JSTCT Transplant Complications Working Group (2022)
  • Author(s): Kimura Shun-ichi、Kameda Kazuaki、Harada Kaito、...、Nakasone Hideki
  • Journal Title: Transplantation and Cellular Therapy Volume: 28 Issue: 4 Pages: 209.e1-209.e9
  • DOI: 10.1016/j.jtct.2021.12.020
  • Peer Reviewed
• [Journal Article] Emergence of clone with PHF6 nonsense mutation in chronic myelomonocytic leukemia at relapse after allogeneic HCT (2022)
  • Author(s): Akahoshi Yu、Nakasone Hideki、Kusuda Machiko、Kameda Kazuaki、Nakamura Yuhei、Kawamura Masakatsu、Takeshita Junko、Kawamura Shunto、Yoshino Nozomu、Misaki Yukiko、Yoshimura Kazuki、Matsumi Shimpei、Gomyo Ayumi、Tanihara Aki、Tamaki Masaharu、Kimura Shun-ichi、Kako Shinichi、Kanda Yoshinobu
  • Journal Title: International Journal of Hematology Volume: 115 Issue: 5 Pages: 748-752
  • DOI: 10.1007/s12185-021-03284-7
  • Peer Reviewed
• [Journal Article] Neutropenia in the First Cycle of Consolidation Chemotherapy with High-Dose Cytarabine Is Not Associated with the Incidence of Relapse in Adult Acute Myeloid Leukemia Patients in First Complete Remission (2022)
  • Author(s): Kimura Shun-ichi、Nakamura Yuhei、Kawamura Masakatsu、Takeshita Junko、Kawamura Shunto、Yoshino Nozomu、Misaki Yukiko、Yoshimura Kazuki、Matsumi Shimpei、Gomyo Ayumi、Okada Yosuke、Akahoshi Yu、Tamaki Masaharu、Kusuda Machiko、Kameda Kazuaki、...i、Kanda Yoshinobu
  • Journal Title: Acta Haematologica Volume: - Issue: 4 Pages: 404-411
  • DOI: 10.1159/000522037
  • Peer Reviewed
• [Journal Article] Human hepatocyte-derived extracellular vesicles attenuate the carbon tetrachloride-induced acute liver injury in mice (2021)
  • Author(s): Kakizaki Masatoshi、Yamamoto Yuichiro、Nakayama Shunya、Kameda Kazuaki、Nagashima Etsuko、Ito Masatoshi、Suyama Takashi、Matsuzaki Yumi、Chiba Tetsuhiro、Sumiyoshi Hideaki、Inagaki Yutaka、Kotani Ai
  • Journal Title: Cell Death and Disease Volume: 12 Issue: 11 Pages: 1010-1010
  • DOI: 10.1038/s41419-021-04204-7
  • Peer Reviewed / Open Access
• [Journal Article] Features of repertoire diversity and gene expression in human cytotoxic T cells following allogeneic hematopoietic cell transplantation (2021)
  • Author(s): Nakasone Hideki、Kusuda Machiko、Terasako-Saito Kiriko、Kawamura Koji、Akahoshi Yu、Kawamura Masakatsu、Takeshita Junko、Kawamura Shunto、Yoshino Nozomu、Yoshimura Kazuki、Misaki Yukiko、Gomyo Ayumi、Kameda Kazuaki、Tamaki Masaharu、Tanihara Aki、Kimura Shun-ichi、Kako Shinichi、Kanda Yoshinobu
  • Journal Title: Communications Biology Volume: 4 Issue: 1 Pages: 1177-1177
  • DOI: 10.1038/s42003-021-02709-7
  • Peer Reviewed
• [Journal Article] Chronic liver graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients during tapering or after stopping calcineurin inhibitors (2021)
  • Author(s): Yoshimura Kazuki、Kimura Shun-ichi、Kawamura Masakatsu、Kawamura Shunto、Takeshita Junko、Yoshino Nozomu、Misaki Yukiko、Gomyo Ayumi、Matsumi Shimpei、Akahoshi Yu、Tamaki Masaharu、Kusuda Machiko、Kameda Kazuaki、...i、Kanda Yoshinobu
  • Journal Title: International Journal of Hematology Volume: 114 Issue: 6 Pages: 674-681
  • DOI: 10.1007/s12185-021-03202-x
  • Peer Reviewed
• [Journal Article] Association between the kinetics of cytomegalovirus reactivation in terms of the area under the curve of cytomegalovirus antigenemia and non‐relapse mortality after allogeneic hematopoietic stem cell transplantation (2021)
  • Author(s): Takeshita Junko、Kimura Shun‐ichi、Nakasone Hideki、Kawamura Shunto、Nakamura Yuhei、Kawamura Masakatsu、Yoshino Nozomu、Misaki Yukiko、Yoshimura Kazuki、Matsumi Shimpei、Gomyo Ayumi、Tamaki Masaharu、Akahoshi Yu、Kusuda Machiko、Kameda Kazuaki、Wada Hidenori、Sato Miki、Kako Shinichi、Kanda Yoshinobu
  • Journal Title: Transplant Infectious Disease Volume: 23 Issue: 5
  • DOI: 10.1111/tid.13715
  • Peer Reviewed
• [Journal Article] Body Weight Loss Before Allogeneic Hematopoietic Stem Cell Transplantation Predicts Survival Outcomes in Acute Leukemia Patients (2021)
  • Author(s): Tamaki Masaharu、Nakasone Hideki、Nakamura Yuhei、Kawamura Masakatsu、Kawamura Shunto、Takeshita Junko、Yoshino Nozomu、Misaki Yukiko、Yoshimura Kazuki、Matsumi Shinpei、Gomyo Ayumi、Tanihara Aki、Kusuda Machiko、Kameda Kazuaki、Akahoshi Yu、Kimura Shun-ichi、Kako Shinichi、Kanda Yoshinobu
  • Journal Title: Transplantation and Cellular Therapy Volume: 27 Issue: 4 Pages: 340.e1-340.e6
  • DOI: 10.1016/j.jtct.2021.01.006
  • Peer Reviewed
• [Journal Article] Immunity and Vaccination Against Measles, Mumps, and Rubella in Adult Allogeneic Hematopoietic Stem Cell Transplant Recipients (2021)
  • Author(s): Koji Kawamura, Hidenori Wada, Hideki Nakasone, Yu Akahoshi, Shunto Kawamura, Junko Takeshita, Nozomu Yoshino, Yukiko Misaki, Kazuki Yoshimura, Ayumi Gomyo, Masaharu Tamaki, Machiko Kusuda, Kazuaki Kameda, Miki Sato, Aki Tanihara, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
  • Journal Title: Transplantation and Cellular Therapy Volume: - Issue: 5 Pages: 436.e1-436.e8
  • DOI: 10.1016/j.jtct.2021.02.027
  • Peer Reviewed
• [Journal Article] Prediction of Cytomegalovirus Reactivation by Recipient Cytomegalovirus-IgG Titer before Allogeneic Hematopoietic Stem Cell Transplantation (2021)
  • Author(s): Kawamura Shunto、Nakasone Hideki、Takeshita Junko、Kimura Shun-ichi、Nakamura Yuhei、Kawamura Masakatsu、Yoshino Nozomu、Misaki Yukiko、Yoshimura Kazuki、Matsumi Shimpei、Gomyo Ayumi、Akahoshi Yu、Kusuda Machiko、Kameda Kazuaki、Tanihara Aki、Tamaki Masaharu、Kako Shinichi、Kanda Yoshinobu
  • Journal Title: Transplantation and Cellular Therapy Volume: 27 Issue: 8 Pages: 683.e1-683.e7
  • DOI: 10.1016/j.jtct.2021.04.024
  • Peer Reviewed
• [Journal Article] Impact of the patient's body weight on the efficacy and adverse events of valganciclovir for cytomegalovirus reactivation after hematopoietic stem cell transplantation (2020)
  • Author(s): Misaki Yukiko、Kimura Shun‐ichi、Kawamura Masakatsu、..., Kameda Kazuaki、Wada Hidenori、Kawamura Koji、Sato Miki、Terasako‐Saito Kiriko、Tanihara Aki、Nakasone Hideki、Kako Shinichi、Kanda Yoshinobu
  • Journal Title: Transplant Infectious Disease Volume: 22 Issue: 3
  • DOI: 10.1111/tid.13270
  • Peer Reviewed
• [Journal Article] Impact of neutropenia evaluated in terms of the D‐index on invasive fungal disease while on empiric or preemptive antifungal treatment strategy in the early phase after allogeneic hematopoietic stem cell transplantation (2020)
  • Author(s): Kimura Shun‐ichi、Nakamura Yuhei、Kawamura Masakatsu、..., Kameda Kazuaki、Wada Hidenori、Sato Miki、Terasako‐Saito Kiriko、Tanihara Aki、Nakasone Hideki、Kako Shinichi、Kanda Yoshinobu
  • Journal Title: Transplant Infectious Disease Volume: 22 Issue: 6
  • DOI: 10.1111/tid.13409
  • Peer Reviewed
• [Journal Article] Hematopoietic cell infusion‐related adverse events in pediatric/small recipients in a prospective/multicenter study (2020)
  • Author(s): Ikeda Kazuhiko、et al.
  • Journal Title: Transfusion Volume: 60 Issue: 5 Pages: 1015-1023
  • DOI: 10.1111/trf.15786
  • Peer Reviewed
• [Presentation] Autologous or allogeneic hematopoietic cell transplantation for peripheral T-cell lymphoma-not otherwise specified and angioimmunoblastic T-cell lymphoma failing first-line therapy (2021)
  • Author(s): Kazuaki Kameda, Shinichi Kako, Takahiro Fukuda, Naoyuki Uchida, Hikaru Kobayashi, Toshio Wakayama, Emiko Sakaida, Shingo Yano, Kazunori Imada, Junya Kanda, Takafumi Kimura, Tatsuo Ichinohe, Yoshiko Atsuta, Eisei Kondo.
  • Organizer: European Hematology Association 2021
  • Int'l Joint Research
• [Presentation] Hepatic niche leads to aggressive NK-cell leukemia proliferation (2021)
  • Author(s): Kameda K, Miyatake Y, Imadome K, Kanda Y, Kotani A.
  • Organizer: 19th International Symposium on Epstein-Barr Virus and associated diseases (EBV2021)
  • Int'l Joint Research
• [Presentation] Autologous or allogeneic HCT for PTCL-NOS and AITL failing first-line therapy (2021)
  • Author(s): 亀田 和明、賀古 真一、福田 隆浩、内田 直之、小林 光、若山 聡雄、堺田 惠美子、矢野 真吾、今田 和典、諫田 淳也、木村 貴文、一戸 辰夫、熱田 由子、近藤 英生
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Hepatic niche leads to aggressive NK-cell leukemia proliferation (2021)
  • Author(s): 亀田 和明、宮竹 佑治、石田 高司、伊藤 旭、飯田 真介、福原 規子、張替 秀郎、藤岡 優樹、高橋 直人、石田 文宏、川上 史裕、川上 徹、中澤 英之、半田 寛、神田 善伸、幸谷 愛
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Hepatic niche leads to aggressive NK-cell leukemia proliferation (2021)
  • Author(s): 亀田 和明、宮竹 佑治、幸谷 愛
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] Hepatic niche leads to aggressive NK-cell leukemia proliferation (2021)
  • Author(s): Kazuaki Kameda, Yuji Miyatake, Yoshinobu Kanda, Ai Kotani
  • Organizer: 63rd ASH Annual Meeting and Exposition (ASH2021)
  • Int'l Joint Research