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Targeting minimal residual leukemic stem cells

Research Project

Project/Area Number 21H02951
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionKanazawa University

Principal Investigator

Miyamoto Toshihiro  金沢大学, 医学系, 教授 (70343324)

Co-Investigator(Kenkyū-buntansha) 菊繁 吉謙  九州大学, 大学病院, 講師 (40619706)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2023: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Keywords急性白血病 / 白血病幹細胞 / 微小残存病変 / 治療抵抗性 / TIM-3
Outline of Research at the Start

本研究ではTIM-3シグナル阻害療法の開発を見据えて、TIM-3でマークされる治療後に残存する治療抵抗性白血病幹細胞(LSCs)の細胞生物学的特性の解明に取り組む。治療後に残存する極少数のLSCsを直接純化し、genomic解析技術、single cell transcriptome解析により、治療抵抗性残存LSCsの多様性の解明を行う。さらに質量分析装置をベースとした網羅的シグナル解析を行い、治療抵抗性LSCsが依存するシグナル経路の解明に取り組む。これら研究により治療後に残存するTIM-3陽性治療抵抗性LSCsを根絶するための基盤とする。

Outline of Final Research Achievements

Relapse still remains the crucial obstacle for the treatment of AML. We evaluated measurable residual leukemic stem cells (MR-LSC) by utilizing TIM-3 expression, a functional marker of LSC. Gene analysis of CD34+CD38- cells disclosed TIM-3+ cells share patient-specific mutations identical to the initial, remission, and relapsed AML clones, but TIM-3- did not. RNA-seq analysis demonstrated most CD34+ cells at diagnosis/relapse belonged to the same AML-cluster, showing higher LSC-related expression. Notably a tiny population at remission was again distributed within the same AML-cluster. TIM-3 was highly expressed in AML-cluster at diagnosis/relapse as well as remission. Frequency of CD34+CD38-TIM-3+ LSC were enumerated by flowcytometry in patients with remission. Only ~20% who achieved MR-LSClow status relapsed, but ~80% with MR-LSCint/high relapsed. MR-LSC is useful to predict outcomes of AML, and targeting TIM-3 signaling would pave the way for eradicating self-renewing AML-LSC.

Academic Significance and Societal Importance of the Research Achievements

LSCはAML治療抵抗性獲得の中心的な役割を担うが、治療後に微小残存するLSCのみを純化して直接研究対象として残存潜伏する機構を解析することは技術的に困難であった。我々が同定したLSC機能分子TIM-3を指標とすることで全治療期を通して真の治療抵抗へと進展する微小残存LSCを正確に捕捉することが可能となり、LSCが依存する生存機構をシングルセル・マルチオミクス解析で明らかにした。さらにTIM-3シグナルによるLSCの制御機構を解明したことで、CD34+CD38-TIM-3+ LSCを直接標的とした治療開発を行なっている。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (26 results)

All 2024 2023 2022 2021 2020

All Journal Article (19 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 19 results,  Open Access: 16 results) Presentation (5 results) (of which Int'l Joint Research: 2 results,  Invited: 3 results) Book (2 results)

  • [Journal Article] Predictors of impaired antibody response after SARS‐CoV‐2 mRNA vaccination in hematopoietic cell transplant recipients: A Japanese multicenter observational study2023

    • Author(s)
      Mori Yasuo、Wake Atsushi、Iwasaki Hiromi、Eto Tetsuya、Ito Yoshikiyo、Kamimura Tomohiko、Ishitsuka Kenji、Sugita Junichi、Yoshimoto Goichi、Choi Ilseung、Hidaka Tomonori、Ogawa Ryosuke、Takamatsu Yasushi、Miyamoto Toshihiro、Akashi Koichi、Nagafuji Koji
    • Journal Title

      American Journal of Hematology

      Volume: 98 Issue: 1 Pages: 102-111

    • DOI

      10.1002/ajh.26769

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Distinguishing immune-mediated thrombotic thrombocytopenic purpura from septic disseminated intravascular coagulation using plasma levels of haptoglobin and factor XIII activity2023

    • Author(s)
      Yamada Shinya、Asakura Hidesaku、Kubo Masayuki、Sakai Kazuya、Miyamoto Toshihiro、Matsumoto Masanori
    • Journal Title

      Research and Practice in Thrombosis and Haemostasis

      Volume: 7 Issue: 2 Pages: 100076-100076

    • DOI

      10.1016/j.rpth.2023.100076

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] IKZF1-plus alterations are not associated with outcomes in Philadelphia‐positive acute lymphoblastic leukemia patients enrolled in the FBMTG ALL/MRD2008 trial2023

    • Author(s)
      Ito Yoshikiyo、Ozawa Hidetoshi、Eto Tetsuya、Miyamoto Toshihiro、Kamimura Tomohiko、Ogawa Ryosuke、Uchida Naoyuki、Wake Atsusi、Fujisaki Tomoaki、Ohno Yuju、Takase Ken、Okumura Hirokazu、Takamatsu Yasushi、Kawano Noriaki、Akashi Koichi、Nagafuji Koji
    • Journal Title

      European Journal of Haematology

      Volume: 111 Issue: 1 Pages: 103-112

    • DOI

      10.1111/ejh.13972

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TIM-3 signaling hijacks the canonical Wnt/β-catenin pathway to maintain cancer stemness in acute myeloid leukemia2023

    • Author(s)
      Sakoda Teppei、Kikushige Yoshikane、Miyamoto Toshihiro、Irifune Hidetoshi、Harada Takuya、Hatakeyama Kiwamu、Kunisaki Yuya、Kato Koji、Akashi Koichi
    • Journal Title

      Blood Advances

      Volume: - Issue: 10 Pages: 2053-2065

    • DOI

      10.1182/bloodadvances.2022008405

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] <scp>GPAM</scp> mediated lysophosphatidic acid synthesis regulates mitochondrial dynamics in acute myeloid leukemia2023

    • Author(s)
      Irifune Hidetoshi、Kochi Yu、Miyamoto Toshihiro、Sakoda Teppei、Kato Koji、Kunisaki Yuya、Akashi Koichi、Kikushige Yoshikane
    • Journal Title

      Cancer Science

      Volume: 114 Issue: 8 Pages: 3247-3258

    • DOI

      10.1111/cas.15835

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of a third dose of anti-SARS-CoV-2 vaccine in hematopoietic cell transplant recipients: A Japanese multicenter observational study2023

    • Author(s)
      Mori Yasuo、Uchida Naoyuki、Wake Atsushi、Iwasaki Hiromi、Ito Yoshikiyo、Tanimoto Kazushi、Ishitsuka Kenji、Yoshimoto Goichi、Ogawa Ryosuke、Sugita Junichi、Takamatsu Yasushi、Tanimoto Kazuki、Hidaka Tomonori、Miyamoto Toshihiro、Akashi Koichi、Nagafuji Koji
    • Journal Title

      Vaccine

      Volume: 41 Issue: 47 Pages: 6899-6903

    • DOI

      10.1016/j.vaccine.2023.08.066

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Peripheral helper-T-cell-derived CXCL13 is a crucial pathogenic factor in idiopathic multicentric Castleman disease2023

    • Author(s)
      Harada Takuya、Kikushige Yoshikane、Miyamoto Toshihiro、Uno Kazuko、Niiro Hiroaki、Kawakami Atsushi、Koga Tomohiro、Akashi Koichi、Yoshizaki Kazuyuki
    • Journal Title

      Nature Communications

      Volume: 14 Issue: 1 Pages: 6959-6959

    • DOI

      10.1038/s41467-023-42718-0

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Human acute leukemia utilizes branched-chain amino acid catabolism to maintain stemness through regulating PRC2 function2022

    • Author(s)
      Kikushige Yoshikane、Miyamoto Toshihiro、Kochi Yu、Semba Yuichiro、Ohishi Maki、Irifune Hidetoshi、Hatakeyama Kiwamu、Kunisaki Yuya、Sugio Takeshi、Sakoda Teppei、Miyawaki Kohta、Kato Koji、Soga Tomoyoshi、Akashi Koichi
    • Journal Title

      Blood Advances

      Volume: - Issue: 14 Pages: 3592-3603

    • DOI

      10.1182/bloodadvances.2022008242

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL.2022

    • Author(s)
      Miyawaki K, Kato K, Sugio T, Sasaki K, Miyoshi H, Semba Y, Kikushige Y, Mori Y, Kunisaki Y, Iwasaki H, Miyamoto T, Kuo FC, Aster JC, Ohshima K, Maeda T, Akashi K.
    • Journal Title

      Blood Adv.

      Volume: 6 Issue: 7 Pages: 2388-2402

    • DOI

      10.1182/bloodadvances.2021004618

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Real-world treatment patterns and clinical outcomes in patients with AML unfit for first-line intensive chemotherapy.2022

    • Author(s)
      Miyamoto T, Sanford D, Tomuleasa C, Hsiao HH, Olivera LJE, Enjeti AK, Gimenez Conca A, Castillo TBD, Girshova L, Martelli MP, Guvenc B, Delgado A, Duan Y, Garbayo Guijarro B, Llamas C, Lee JH.
    • Journal Title

      Leuk Lymph

      Volume: 63 Issue: 4 Pages: 928-938

    • DOI

      10.1080/10428194.2021.2002321

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ASXL1 mutations with serum EPO levels predict poor response to darbepoetin alfa in lower-risk MDS: W-JHS MDS01 trial.2022

    • Author(s)
      Morita Y, Nannya Y, Ichikawa M, Hanamoto H, Shibayama H, Maeda Y, Hata T, Miyamoto T, Kawabata H, Takeuchi K, Tanaka H, Kishimoto J, Miyano S, Matsumura I, Ogawa S, Akashi K, Kanakura Y, Mitani K.
    • Journal Title

      Int J Hematol

      Volume: 116 Issue: 5 Pages: 659-668

    • DOI

      10.1007/s12185-022-03414-9

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phase I study of alvocidib plus cytarabine/mitoxantrone or cytarabine/daunorubicin for acute myeloid leukemia in Japan2022

    • Author(s)
      Ikezoe T, Ando K, Onozawa M, Yamane T, Hosono N, Morita Y, Kiguchi T, Iwasaki H, Miyamoto T, Matsubara K, Sugimoto S, Miyazaki Y, Kizaki M, Akashi K.
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 12 Pages: 4258-4266

    • DOI

      10.1111/cas.15458

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Outcomes of third allogeneic hematopoietic stem cell transplantation in relapsed/refractory acute leukemia after a second transplantation2021

    • Author(s)
      Kobayashi S., Takahashi S., et al.
    • Journal Title

      Bone Marrow Transplantation

      Volume: 57 Issue: 1 Pages: 43-50

    • DOI

      10.1038/s41409-021-01485-6

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Circulating CD34+?cells of primary myelofibrosis patients contribute to myeloid-dominant hematopoiesis and bone marrow fibrosis in immunodeficient mice2021

    • Author(s)
      Saito Noriyuki、Yamauchi Takuji、Kawano Noriaki、Ono Rintaro、Yoshida Shuro、Miyamoto Toshihiro、Kamimura Tomohiko、Shultz Leonard D.、Saito Yoriko、Takenaka Katsuto、Shimoda Kazuya、Harada Mine、Akashi Koichi、Ishikawa Fumihiko
    • Journal Title

      International Journal of Hematology

      Volume: 115 Issue: 2 Pages: 198-207

    • DOI

      10.1007/s12185-021-03239-y

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical features and chromosomal/genetic aberration in adult acute lymphoblastic leukemia in Japan: results of Fukuoka Blood & Marrow Transplant Group Studies ALL MRD 2002 and 2008.2021

    • Author(s)
      Morishige S, Miyamoto T, Eto T, Uchida N, Kamimura T, Miyazaki Y, Ogawa R, Okumura H, Fujisak T, Iwasaki H, Kawano N, Wake A, Ohta T, Takamatsu Y, Kurokawa T, Ito Y, Maeda T, Akashi K, Nagafuji K
    • Journal Title

      Int J Hematol

      Volume: 113 Issue: 6 Pages: 815-822

    • DOI

      10.1007/s12185-021-03116-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chromosomal defects and survival in adult T cell leukemia/lymphoma patients after allogeneic HSCT.2021

    • Author(s)
      Nakano N, Utsunomiya A, Matsuo K, Yoshida N, Seto M, Ohshima K, Fujiwara H, Fuji S, Takatsuka1 Y, Ito A, Miyamoto T, Suehiro Y, Nakamae H, Sawayama Y, Yuasa M, Miyazaki Y, Ota S, Imada K, Fukuda T, Ichinohe T, Atsuta Y, Kato K.
    • Journal Title

      Blood Advances

      Volume: 5(2) Issue: 2 Pages: 475-486

    • DOI

      10.1182/bloodadvances.2020003639

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Azacitidine for the treatment of patients with relapsed acute myeloid leukemia after allogeneic stem cell transplantation.2021

    • Author(s)
      Yoshimoto G, Mori Y, Kato K, Odawara J, Kuriyama T, Ueno T, Obara T, Yurino A, Yoshida S, Ogawa R, Ohno Y, Iwasaki H, Eto T, Akashi K, Miyamoto T.
    • Journal Title

      Leuk Lymphoma

      Volume: 62 Issue: 12 Pages: 2939-2948

    • DOI

      10.1080/10428194.2021.1941937

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy of prophylactic letermovir for cytomegalovirus reactivation in hematopoietic cell transplantation: a multicenter real-world data2020

    • Author(s)
      Mori Yasuo, et al.
    • Journal Title

      Bone Marrow Transplantation

      Volume: 56 Issue: 4 Pages: 853-862

    • DOI

      10.1038/s41409-020-01082-z

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Outcome predictors after retransplantation in relapsed acute lymphoblastic leukemia: a multicenter, retrospective study2020

    • Author(s)
      Mori Yasuo、Fukuoka Blood and Marrow Transplantation Group、Sasaki Kensuke、Ito Yoshikiyo、Kuriyama Takuro、Ueno Toshiyuki、Kadowaki Masanori、Aoki Takatoshi、Sugio Takeshi、Yoshimoto Goichi、Kato Koji、Maeda Takahiro、Nagafuji Koji、Akashi Koichi、Miyamoto Toshihiro
    • Journal Title

      Annals of Hematology

      Volume: 100 Issue: 1 Pages: 197-208

    • DOI

      10.1007/s00277-020-04310-0

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 新規分子標的薬時代における真菌症マネージメント2024

    • Author(s)
      宮本敏浩
    • Organizer
      第46回日本造血・免疫細胞療法学会・シンポジウム
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Prevalence and Outcome of Vexas Syndrome in Unrelated Hematopoietic Stem Cell Transplantation Suppressed expression of ASCT1 contributes to the maintenance of leukemia stemness via the enhancement of antioxidant capacity.2023

    • Author(s)
      Zaimoku Y, Imi T, Hatada T, Mura H, Yoshino H, Tran DCC, Nannya Y, Ogawa S, Hosomichi K, Doki N, Katayama Y, Koike T, Matsuoka K, Nishida T, Takahashi Y, Kataoka K, Nakazawa H, Ueda Y, Fukuda T, Ichinohe T, Ishimaru F, Onizuka M, Atsuta Y, Miyamoto T.
    • Organizer
      65th ASH meeting
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Single-Cell Dissection Reveals a Distinct Origin of Small Paroxysmal Nocturnal Hemoglobinuria Clones in Immune Aplastic Anemia and Healthy Individuals.2023

    • Author(s)
      Tran DCC , Zaimoku Y, Hosomichi K, mizumaki H, Hosokawa K, Yamazaki H, Miyamoto T , Nakao S.
    • Organizer
      65th ASH meeting
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 急性骨髄性白血病の新規治療2022

    • Author(s)
      宮本敏浩
    • Organizer
      第22回日本薬学会Pharmoco-Hematologyシンポジウム
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] クローン性造血に潜む内科併存疾患2022

    • Author(s)
      宮本敏浩
    • Organizer
      第86回日本内科学会北陸支部生涯教育講演会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Book] 血液症候群・後天性再生不良性貧血2023

    • Author(s)
      細川晃平、宮本敏浩
    • Total Pages
      546
    • Publisher
      日本臨床社
    • Related Report
      2023 Annual Research Report
  • [Book] 血液症候群・再生不良性貧血-発作性夜間ヘモグロビン尿症症候群2023

    • Author(s)
      細川晃平、宮本敏浩
    • Total Pages
      546
    • Publisher
      日本臨床社
    • Related Report
      2023 Annual Research Report

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Published: 2021-04-28   Modified: 2025-01-30  

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