Harnessing the single-cell biology and biomarker involving in the therapeutic response of patients with severe acute graft-versus-host disease undergoing mesenchymal stem cell transfusion

• Project/Area Number: 19K16605
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Yokoyama Kazuaki 東京大学, 医科学研究所, 助教 (00647498)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥130,000 (Direct Cost: ¥100,000、Indirect Cost: ¥30,000); Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
• Keywords: 造血幹細胞移植 / 急性移植片対宿主病 / 1細胞RNAシーケンス解析 / 間葉系幹細胞 / シングルセル解析 / １細胞RNAシーケンス / シングルセルRNA解析

Outline of Research at the Start

造血幹細胞移植において、合併症である急性移植片対宿主病 (aGVHD)克服は課題である。特に１次治療のステロイド抵抗例は予後不良であり、その克服法の確立は急務である。近年、ステロイド抵抗性aGVHD例に間葉系幹細胞(MSC)療法が高い奏功率を示す事が報告されているが、1)生体内での作用機序が不明、2)治療反応バイオマーカーが存在しない、という致命的な問題がある。本研究では、MSC療法を受けたaGVHD患者を対象とした、治療前後の末梢血細胞の１細胞RNA解析を行い、MSCが誘導していると考えられる、未知のaGVHD制御に関わる免疫細胞集団を同定し、MSC療法のaGVHD制御作用機序の解明と、治療反応バイオマーカーの発見を目指す。

Outline of Final Research Achievements

Severe acute graft-versus-host disease (aGVHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (alloSCT) for treatment of hematological disease. This is true for the patients with steroid-refractory aGVHD.Human mesenchymal stem cells (MSC)transfusion represents one of the most effective salvage therapy for patients with steroid-refractory aGVHD. However, the main problem of MSC therapy is that the there is no therapeutic biomarker.To this aim, we performed single cell RNA analysis of the peripheral blood mononuclear cells before and after MSC infusion from patients with aGVHD. As a result, we found the candidate aGVHD-regulatory cells with their transcriptome with putative biomarkers, A and B. This will be able to elucidate aGVHD regulatory cells, which will lead to establishment of therapeutic biomarkers for patients with aGVHD undergoing MSC transfusion.

Academic Significance and Societal Importance of the Research Achievements

造血幹細胞移植は、急性白血病などの難治性血液疾患の根治的治療法の一つとして確立されているが、合併症として急性移植片対宿主病(aGVHD)が課題である。を克服する事に繋がり得る。近年、間葉系幹細胞(MSC)療法が注目されているがその生体内での作用機序とバイオマーカーが不明である。そこで本研究では、MSC療法を受けたaGVHD患者を対象 とした、治療前後の末梢血免疫細胞の1細胞RNAシーケンス解析を行うことで、MSCが誘導していると考えられる、未知のaGVHD制御に関わる免疫細胞集団候補とバイオマーカ候補としてA,Bを同定した。これによりMSCの治療反応バイオマーカーの確立に繋がる。

Research Products

• [Journal Article] 急性骨髄性白血病や骨髄異形成症候群において同種移植後の循環腫瘍DNA残存は再発を予測するバイオマーカーである (2021)
  • Author(s): 横山和明
  • Journal Title: 臨床血液 Volume: in press
  • NAID: 130008063721
  • Peer Reviewed
• [Journal Article] Comprehensive molecular analysis of genomic profiles and PD-L1 expression in lung adenocarcinoma with a high-grade fetal adenocarcinoma component (2021)
  • Author(s): Masaki Suzuki, Rika Kasajima, Tomoyuki Yokose, Hiroyuki Ito, Eigo Shimizu, Seira Hatakeyama, Kazuaki Yokoyama, Rui Yamaguchi, Yoichi Furukawa, Satoru Miyano, Seiya Imoto, Emi Yoshioka, Kota Washimi, Yoichiro Okubo, Kae Kawachi, Shinya Sato, Yohei Miyagi
  • Journal Title: Translational Lung Cancer Research Volume: 10 Issue: 3 Pages: 1292-1304
  • DOI: 10.21037/tlcr-20-1158
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High Prevalence of Left Ventricular Non-Compaction and Its Effect on Chemotherapy-Related Cardiac Dysfunction in Patients With Hematological Diseases (2020)
  • Author(s): Hirano M, Kimura K, Ishigaki T, Nojima M, Daimon M, Morita H, Takenaka K, Xu B, Sawada N, Hirokawa M, Komuro I, Morisaki T, Yotsuyanagi H, Kawamata T, Yokoyama K, Konuma T, Kato S, Yasui H, Nagamura-Inoue T, Uchimaru K, Takahashi S, Imai Y, Tojo A.
  • Journal Title: Circulation Journal Volume: 84 Issue: 11 Pages: 1957-1964
  • DOI: 10.1253/circj.CJ-20-0344
  • NAID: 130007928999
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2020-10-23
  • Peer Reviewed / Open Access
• [Journal Article] The EGFL7-ITGB3-KLF2 axis enhances survival of multiple myeloma in preclinical models. (2020)
  • Author(s): Salama Y, Andries H, Yokoyama K, Takahashi S Hattori K and Heissig B,.
  • Journal Title: Blood Adv Volume: in press Issue: 6 Pages: 1021-1037
  • DOI: 10.1182/bloodadvances.2019001002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Successful clinical sequencing by molecular tumor board in an elderly patient with refractory Sezary syndrome (2020)
  • Author(s): Hijikata K, Yokoyama K (co-1st and co-corresponding author), Yokoyama N, Matsubara Y, Shimizu E, Nakashima M, Yamagishi M, Ota Y, Lim L, Yamaguchi R, Ito M, Tanaka Y, Denda T, Tani K, Yotsuyanagi H, Imoto S, Miyano S, Uchimaru K, Tojo A.
  • Journal Title: JCO Precis Oncol Volume: 4 Issue: 4 Pages: 534-560
  • DOI: 10.1200/po.19.00254
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Artificial intelligence-guided precision medicine in hematological disorders (2020)
  • Author(s): 横山 和明
  • Journal Title: Rinsho Ketsueki Volume: 61 Issue: 5 Pages: 554-563
  • DOI: 10.11406/rinketsu.61.554
  • NAID: 130007852311
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Clinical features and outcomes of adult Langerhans cell histiocytosis: a single-center experience (2020)
  • Author(s): Kobayashi Masayuki、Ando Shohei、Kawamata Toyotaka、Makiyama Junya、Yokoyama Kazuaki、Imai Yoichi、Tojo Arinobu
  • Journal Title: International Journal of Hematology Volume: 112 Issue: 2 Pages: 185-192
  • DOI: 10.1007/s12185-020-02892-z
• [Journal Article] Immunophenotypic analysis of cerebrospinal fluid reveals concurrent development of ATL in the CNS of a HAM/TSP patient. (2020)
  • Author(s): Takeda R, Ishigaki T, Ohno N, Yokoyama K, Kawamata T, Fukuyama T, Araya N, Yamano Y, Uchimaru K, Tojo A.
  • Journal Title: Int J Hematol Volume: 111(6) Issue: 6 Pages: 891-896
  • DOI: 10.1007/s12185-019-02815-7
  • Peer Reviewed / Open Access
• [Journal Article] 血液がんのプレシジョン・メディスンにおけるAI活用の試み (2020)
  • Author(s): 横山和明
  • Journal Title: 臨床血液 Volume: 61 Pages: 1-10
  • NAID: 130007852311
  • Peer Reviewed
• [Journal Article] An Unusually Short Latent Period of Therapy-Related Myeloid Neoplasm Harboring a Rare MLL-EP300 Rearrangement: Case Report and Literature Review (2019)
  • Author(s): Takeda R, Yokoyama K (corresponding author), Kobayashi S, Kawamata T, S Nakamura, Tomofusa F, Ito M, Yusa N, Shimizu E, Ohno N, Yamaguchi R, Imoto S, Miyano S, Uchimaru K, and Tojo A.
  • Journal Title: Case Rep Hematol Volume: epub Pages: 4532434-4532434
  • DOI: 10.1155/2019/4532434
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic impact of circulating tumor DNA status post-allogeneic hematopoietic stem cell transplantation in AML and MDS. (2019)
  • Author(s): Nakamura S, Yokoyama K (co-1st and co-corresponding author), Shimizu E, Yusa N, Kondoh K, Ogawa M, Takei T, Kobayashi A, Ito M, Isobe M, Konuma T, Kato S, Kasajima R, Wada Y, Inoue-Nagamura T, Yamaguchi R, Takahashi S, Imoto S, Miyano S, and Tojo A.
  • Journal Title: Blood Volume: 133 Issue: 25 Pages: 2682-2695
  • DOI: 10.1182/blood-2018-10-880690
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The first case of elderly TCF3-HLF-positive B-cell acute lymphoblastic leukemia. (2019)
  • Author(s): Takeda R, Yokoyama K (corresponding author), Ogawa M, Kawamata T, Tomofusa F, Kondoh K, Tomomi T, Nakamura S, Ito M, Yusa N, Shimizu E, Ohno N, Uchimaru K, Yamaguchi R, Imoto S, Miyano S, and Tojo A.
  • Journal Title: Leuk lymphoma. Volume: 60 Issue: 11 Pages: 2821-2824
  • DOI: 10.1080/10428194.2019.1602267
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 血液がんのプレシジョン・メディスンにおけるAI活用の試み (2019)
  • Author(s): 横山和明
  • Organizer: 第81回日本血液学会学術集会 Presidential シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] 腫瘍由来循環DNAを用いたAMLおよびMDSの移植後微小残存病変検出に関する後方視的解析 (2019)
  • Author(s): 横山和明
  • Organizer: 神奈川移植Forum
  • Invited
• [Presentation] 治療関連骨髄系腫瘍15例のゲノム解析と液体生検によるファウンダークローンの後方視的追跡 (2019)
  • Author(s): 近藤 幹也, 横山 和明, 遊佐 希, 伊藤 美香, 清水 英悟, 中村 聡介, 小川 弥穂, 武井 智美, 小林 麻子, 笠島 理加, 和田 結花, 山口 類, 井元 清哉, 長村 登紀子, 内丸 薫, 宮野 悟, 東條 有伸
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 臨床シークエンスにて確定診断に至った慢性好中球性白血病の２例 (2019)
  • Author(s): 小川 弥穂, 横山 和明, 塚田 信弘, 余語 孝夫3, 近藤 幹也, 武井 智美, 中村 聡介, 伊藤 美香, 小林 麻子, 遊佐 希, 山本 茉子, 笠島 理加, 清水 英悟, 山口 類, 井元 清哉, 宮野 悟, 東條 有伸
  • Organizer: 第81回日本血液学会学術集会 Presidential シンポジウム
• [Presentation] Cell free-DNA based detection of minimal residual disease post allogenic-stem cell transplantation in acute myeloid leukemia and myelodysplastic syndromes (2019)
  • Author(s): 1.Kazuaki Yokoyama, Nozomi Yusa, Mika Ito, Miho Ogawa, Kanya Kondoh, Eigo Shimizu, Seiya Imoto, Arinobu Tojo, Satoshi Takahashi
  • Organizer: 7th US-Japan Workshop on Biomarkers for Cancer Early Detection (AMED-NCI)
  • Int'l Joint Research
• [Presentation] The utility of exome sequence of circulating tumor DNA in drug-resistant and/or advanced phase chronic myeloid leukemia (2019)
  • Author(s): omomi Takei, Kazuaki Yokoyama, Sousuke Nakamura, Miho Ogawa, Kanya Kondoh, Eigo Shimizu, Rika Kasajima, Rui Yamaguchi, Seiya Imoto, Satoru Miyano, Arinobu Tojo
  • Organizer: The 78th Annual Meeting of the Japanese Cancer Association
  • Int'l Joint Research