Elucidation of the molecular mechanism of POEMS syndrome by single cell analysis of bone marrow plasma cells

• Project/Area Number: 18K08338
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: International University of Health and Welfare
• Principal Investigator: Nakaseko Chiaki 国際医療福祉大学, 医学部, 主任教授 (30323398)
• Co-Investigator(Kenkyū-buntansha): 三村 尚也 千葉大学, 医学部附属病院, 講師 (00422220) ; 塚本 祥吉 千葉大学, 医学部附属病院, 特任助教 (00814617) ; 武内 正博 千葉大学, 医学部附属病院, 講師 (50466702) ; 堺田 恵美子 千葉大学, 大学院医学研究院, 准教授 (60422218) ; 竹田 勇輔 千葉大学, 医学部附属病院, 助教 (60772746) ; 大和田 千桂子 千葉大学, 大学院医学研究院, 講師 (80436352)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: POEMS症候群 / シングルセル解析 / RNAシーケンス / VEGF / MHC class II / Osteopontin / 形質細胞腫瘍 / 次世代シークエンサー / POEMS syndrome / 形質細胞 / 次世代シーケンサー

Outline of Final Research Achievements

POEMS syndrome is a rare monoclonal plasma cell (PC) disorder with unique symptoms distinct from other plasma cell neoplasms, including high serum VEGF levels. We performed the single-cell RNA sequencing of BM PCs from patients with POEMS syndrome and identified POEMS clones that had immunoglobulin λ light chain (IGL) sequences (IGLV1-36, 40, 44, and 47) specific to POEMS syndrome. The proportions of POEMS clones in PCs were markedly smaller (median: 12.9%) than in multiple myeloma (MM) (96-100%) and MGUS patients (57-81%). Single-cell transcriptomes revealed that POEMS clones were CD19-negative, CD138-positive, and MHC class II-low, which allowed for their prospective isolation. POEMS clones expressed significantly lower levels of c-MYC and CCND1 than MM and MGUS. VEGF mRNA was not up-regulated in POEMS clones, indicating that VEGF is not produced by POEMS clones. These results reveal unique features of POEMS clones and enhance our understanding of the pathogenesis of POEMS syndrome.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果によりPOEMS症候群におけるクローン性形質細胞の性質を明らかにすることができ，フローサイトメトリーによってクローン性形質細胞を同定する手法を確立することが出来た。その手法を用いて治療後の効果判定として骨髄中微小残存病変を評価することが可能となった。本症候群の病態として高VEGF血症が中心的な役割を果たしているが，骨髄中クローン性形質細胞はVEGFを直接的に産生していないことを示すことが出来た。これらの研究成果は，極めて難治性でADLが著しく障害される難病であるPOEMS症候群に対して，新たな治療戦略を開発するための基礎的かつ重要なデータとなる。

Research Products

• [Journal Article] Identification of clonal immunoglobulin λ light-chain gene rearrangements in AL amyloidosis using next-generation sequencing (2021)
  • Author(s): Kimura K、Tsukamoto S、Miyazaki K、Kawajiri-Manako C、Ishii A、Rahmutulla B、Fukuyo M、Oshima-Hasegawa N、Mitsukawa S、Takeda Y、Mimura N、Takeuchi M、Ohwada C、Iseki T、Matsusaka K、Sanada M、Yokote K、Kaneda A、Ishida T、Suzuki K、Nakaseko C、Sakaida E
  • Journal Title: Experimental Hematology Volume: 101-102 Pages: 34-41
  • DOI: 10.1016/j.exphem.2021.08.001
  • Peer Reviewed / Open Access
• [Journal Article] The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells. (2021)
  • Author(s): Nagai Y, Mimura N, Nakaseko C et al
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 2074-2074
  • DOI: 10.1038/s41598-021-81577-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic subtype classification using a simplified algorithm and mutational characteristics of diffuse large B‐cell lymphoma in a Japanese cohort (2021)
  • Author(s): Mishina T、Oshima‐Hasegawa N、Tsukamoto S、Fukuyo M、Kageyama H、Muto T、Mimura N、Rahmutulla B、Nagai Y、Kayamori K、Hino Y、Mitsukawa S、Takeda Y、Ohwada C、Takeuchi M、Tsujimura H、Iseki T、Nakaseko C、Ikeda J、Itami M、Yokote K、Ohara O、Kaneda A、Sakaida E
  • Journal Title: British Journal of Haematology Volume: 195 Issue: 5 Pages: 731-742
  • DOI: 10.1111/bjh.17765
  • Peer Reviewed
• [Journal Article] Pharmacokinetically guided, once-daily intravenous busulfan in combination with fludarabine for elderly AML/MDS patients as a conditioning regimen for allogeneic stem cell transplantation (2021)
  • Author(s): Ohwada C、Yamazaki S、Shono K、Kayamori K、Hino Y、Oshima-Hasegawa N、Muto T、Tsukamoto S、Mitsukawa S、Takeda Y、Mimura N、Takeuchi M、Iseki T、Onoda M、Yokota A、Suzuki T、Ishii I、Nakaseko C、Sakaida E
  • Journal Title: International Journal of Hematology Volume: 114 Issue: 6 Pages: 664-673
  • DOI: 10.1007/s12185-021-03188-6
  • Peer Reviewed
• [Journal Article] Elevated TAT in COVID-19 Patients with Normal D-Dimer as a Predictor of Severe Respiratory Failure: A Retrospective Analysis of 797 Patients (2021)
  • Author(s): Takeshita Y、Terada J、Hirasawa Y、Kinoshita T、Tajima H、Koshikawa K、Kinouchi T、Isaka Y、Shionoya Y、Fujikawa A、Tada Y、Nakaseko C、Tsushima K
  • Journal Title: Journal of Clinical Medicine Volume: 11 Issue: 1 Pages: 134-134
  • DOI: 10.3390/jcm11010134
• [Journal Article] Successful allogeneic bone marrow transplantation after massive gastrointestinal bleeding in a patient with myelodysplastic syndrome associated with intestinal Beh?et-like disease (2021)
  • Author(s): Ishii A、Tsukamoto S、Mishina T、Izumi S、Nagai Y、Yamazaki M、Hino Y、Kayamori K、Oshima-Hasegawa N、Muto T、Mitsukawa S、Takeda Y、Mimura N、Ohwada C、Nakaseko C、Ikeda J、Sakaida E
  • Journal Title: Leukemia Research Reports Volume: 16 Pages: 100278-100278
  • DOI: 10.1016/j.lrr.2021.100278
  • Peer Reviewed
• [Journal Article] Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone therapy increases carotid intima-media thickness and plaque score with von Willebrand factor activity elevation in patients with malignant lymphoma (2021)
  • Author(s): Shimizu N、Ngayama D、Watanabe Y、Yamaguchi T、Nakamura S、Ohira M、Saiki A、Onda H、Yamaoka S、Abe K、Nakaseko C、Tatsuno I
  • Journal Title: Journal of Chemotherapy Volume: Epub Issue: 4 Pages: 1-6
  • DOI: 10.1080/1120009x.2021.1988202
  • Peer Reviewed
• [Journal Article] High presepsin concentrations in bile and its marked elevation in biliary tract diseases: A retrospective analysis (2021)
  • Author(s): Yamaguchi T、Ohira M、Kawagoe N、Nakamura S、Tanaka S、Oka R、Watanabe Y、Sato Y、Nagayama D、Saiki A、Matsuzawa Y、Bujo H、Terai K、Hiruta N、Tatsuno I、Nakaseko C、Kikuchi H、Matsuoka K、Yokota H、Shimizu N
  • Journal Title: Clinica Chimica Acta Volume: 521 Pages: 278-284
  • DOI: 10.1016/j.cca.2021.07.025
  • Peer Reviewed
• [Journal Article] Successful second autologous stem-cell transplantation for patients with relapsed and refractory POEMS syndrome. (2021)
  • Author(s): Shibamiya A, Ohwada C, Ishii A, Nakaseko C, et al.
  • Journal Title: Bone Marrow Transplant Volume: 56 Issue: 2 Pages: 517-520
  • DOI: 10.1038/s41409-020-01024-9
  • Peer Reviewed
• [Journal Article] POEMS症候群に特徴的な免疫グロブリン軽鎖変異パターン (2021)
  • Author(s): 一色佑介，三村尚也，塚本祥吉，堺田惠美子，中世古知昭
  • Journal Title: 血液内科 Volume: in press
  • NAID: 40022600467
  • Peer Reviewed
• [Journal Article] Genetic and transcriptional landscape of plasma cells in POEMS syndrome (2019)
  • Author(s): Nagao Y, Mimura N, Takeda J, Yoshida K, Shiozawa Y, Oshima M, Aoyama K, Nishijima D, Isshiki Y, Kayamori K, Kawajiri-Manako C, Oshima-Hasegawa N, Tsukamoto S, Mitsukawa S, Takeda Y, Ohwada C, Takeuchi M, Iseki T, Misawa S, Miyano S, Ohara O, Yokote K, Sakaida E, Kuwabara S, Sanada M, Iwama A, Ogawa S, Nakaseko C.
  • Journal Title: Leukemia Volume: － Issue: 7 Pages: 1723-1735
  • DOI: 10.1038/s41375-018-0348-x
  • Peer Reviewed / Open Access
• [Journal Article] POEMS syndrome: advances in molecular pathophysiology and treatment (2019)
  • Author(s): Nakaseko C
  • Journal Title: Rinsho Ketsueki Volume: 60 Issue: 8 Pages: 979-987
  • DOI: 10.11406/rinketsu.60.979
  • NAID: 130007702166
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] 特集「全身性疾患と腎update」 第5章 血液疾患 4. POEMS諸侯群（Crow-Fukase症候群）・血液専門医の立場より (2019)
  • Author(s): 中世古知昭
  • Journal Title: 腎と透析 Volume: 86 Pages: 299-301
• [Journal Article] POEMS症候群の形質細胞における遺伝子異常 (2019)
  • Author(s): 三村尚也、堺田惠美子、中世古知昭
  • Journal Title: 腫瘍内科 Volume: 24 Pages: 691-696
  • NAID: 40022108670
• [Presentation] POEMS症候群の分子病態の解明と治療の進歩 (2022)
  • Author(s): Nakaseko C
  • Organizer: 第47回日本骨髄腫学会学術集会
  • Invited
• [Presentation] マルチパラメータフローサトメトリーによるＰＯＥＭＳ症候群のクローン性形質細胞の検出 (2022)
  • Author(s): 石井改，塚本祥吉, 三村尚也, 長井友莉恵，一色祐介，松井愼一郎，中尾三四郎，柴宮明日香，日野祐太郎, 栢森健介, 大島渚, 武藤朋也, 三川紫緒, 竹田勇輔, 水地智基，三澤園子，大和田千桂子，横手幸太郎，桑原聡，中世古知昭, 高松博幸，堺田惠美子
  • Organizer: 第47回日本骨髄腫学会学術集会
• [Presentation] Detection of Clonal Plasma Cells in POEMS Syndrome Using Multiparameter Flow Cytometry (2021)
  • Author(s): Ishii A, Tsukamoto S, Mimura N, Nagai Y, Matsui S, Nakao S, Shibamiya A, Hino Y, Kayamori K, Oshima-Hasegawa N, Muto T, Mitsukawa S, Takeda Y, Suichi , Misawa S, Ohwada C, Yokote K, Kuwabara S, Nakaseko C, Takamatsu H, Sakaida E
  • Organizer: 63rd ASH Annual Meeting and Exposition
• [Presentation] 移植適応多発性骨髄腫における初回採取レジメンによる自家末梢血幹細胞採取不良例の解析 (2021)
  • Author(s): 三村尚也, 長井友莉恵, 塚田信弘,青墳信之, 李政樹, 勝岡優奈, 若山聡雄, 鈴木利貴央, 尾崎修治, 村上博和, 中世古知昭, 堺田惠美子.
  • Organizer: 日本輸血・細胞治療学会総会
• [Presentation] POEMS症候群のクローナル形質細胞に特有な遺伝子発現と表面マーカーの同定 (2021)
  • Author(s): 一色佑介, 大島基彦, 三村尚也, 栢森健介, 長井友莉恵, 関真秀, 中島やえ子, 武藤朋也, 塚本祥吉, 竹田勇輔, 大和田千桂子, 三澤園子, 池田純一郎, 真田昌, 桑原聡, 鈴木穣, 堺田惠美子, 中世古知昭, 岩間厚志
  • Organizer: 第83回日本血液学会総会
• [Presentation] Utxの喪失はBrafV600E変異と協調して多発性骨髄腫様疾患を誘発する (2021)
  • Author(s): Ola Rizq, 三村尚也, 小出周平, モハメド リズク, 大島基彦, 百瀬修二, 中島やえ子, 青山和正, 更屋敦則, 井関徹, 堺田惠美子, 中世古知昭, 奥野豊, 田丸淳一, 本田浩章, 岩間厚志
  • Organizer: 第83回日本血液学会総会
• [Presentation] 骨髄形質細胞シングルセル解析によるPOEMS症候群の分子病態の解明 (2021)
  • Author(s): 中世古知昭, 織谷健司, 森直樹, 大和田千桂子, 渡部玲子, 東ヶ崎絵美, 桐戸敬介, 塚本祥吉, 三村尚也, 堺田恵美子
  • Organizer: 国際医療福祉大学学会
• [Presentation] Single plasma cell transcriptome analysis in POEMS syndrome. (2020)
  • Author(s): Isshiki Y, Mimura N, Nakaseko C et al.
  • Organizer: The European Hematology Association Congress 2020
  • Int'l Joint Research
• [Presentation] Single-cell analyses unravel unique features of plasma cell clones in POEMS syndrome. (2020)
  • Author(s): Isshiki Y, Mimura N, Nakaseko C et al.
  • Organizer: The 62nd Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Presentation] Single plasma cell transcriptome analysis in POEMS syndrome. (2020)
  • Author(s): Yusuke Isshiki, Naoya Mimura, Motohiko Oshima, Kensuke Kayamori, Masahide Seki, Kiyomi Imamura, Terumi Horiuchi, Yurie Nagai, Shokichi Tsukamoto, Yusuke Takeda, Chikako Ohwada, Sonoko Misawa, Satoshi Kuwabara, Yutaka Suzuki, Emiko Sakaida, Chiaki Nakaseko, Atsushi Iwama.
  • Organizer: 25th Congress of European Hematology Association
  • Int'l Joint Research
• [Presentation] 自家移植後再燃 POEMS 症候群に対し複数回移植は有用である (2020)
  • Author(s): 松井慎一郎、大和田千桂子、相関祥穂、塩入勇翔、礒貝俊太郎、中尾三四郎、柴宮明日香、石井改、山﨑美貴、三科達三、長井友莉恵、日野裕太郎、木村賢司、栢森健介、大島渚、塚本祥吉、三川紫緒、竹田勇輔、三村尚也、武内正博、井関徹、中世古知昭、堺田惠美子
  • Organizer: 第42回日本造血細胞移植学会総会
• [Presentation] 再発POEMS症候群に対する再移植の有用性 (2019)
  • Author(s): 柴宮明日香、大和田千桂子、松井愼一郎、中尾三四郎、石井改、長井友莉恵、三科達三、山崎美貴、一色佑介、高石浩司、木村賢司、大島渚、塚本祥吉、竹田勇輔、三川紫緒、三村尚也、武内正博、井関徹、三澤園子、桑原聡、中世古知昭、堺田惠美子
  • Organizer: 第81回日本血液学会総会
• [Presentation] POEMS症候群の克服にむけて～分子病態解明と新規治療法の確立 (2018)
  • Author(s): 中世古知昭
  • Organizer: 第43回日本骨髄腫学会学術集会 会長講演
  • Invited
• [Presentation] POEMS症候群における形質細胞の網羅的遺伝子解析 (2018)
  • Author(s): 三村尚也
  • Organizer: 第43回日本骨髄腫学会学術集会 シンポジウム
  • Invited
• [Presentation] POEMS症候群に対する自家末梢血幹細胞移植療法 (2018)
  • Author(s): 堺田惠美子
  • Organizer: 第43回日本骨髄腫学会学術集会 シンポジウム
  • Invited
• [Presentation] Molecular analysis of pathophysiology and recent advances in the treatment of POEMS syndrome (2018)
  • Author(s): 中世古知昭
  • Organizer: 第80回日本血液学会総会 シンポジウム
  • Invited
• [Presentation] 形質細胞腫瘍の診断と治療の進歩 (2018)
  • Author(s): 中世古知昭
  • Organizer: 第19回日本検査血液学会学術集会 教育講演
  • Invited