Analysis of novel pathogenesis caused by disorder of immature hematopoietic cells in multiple myeloma

• Project/Area Number: 16K09862
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kindai University
• Principal Investigator: TANAKA Hirokazu 近畿大学, 医学部, 講師 (40360846)
• Co-Investigator(Kenkyū-buntansha): 松村 到 近畿大学, 医学部, 教授 (00294083) ; 頼 晋也 近畿大学, 医学部, 講師 (70460855) ; 森田 泰慶 近畿大学, 医学部, 講師 (80411594)
• Research Collaborator: SERIZAWA kentaro
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 多発性骨髄腫 / 腫瘍幹細胞 / 表面抗原 / 薬剤感受性 / 分子標的 / 幹細胞

Outline of Final Research Achievements

We isolated myeloma initiating cells from phenotypically defined CD38+ CD 138+ CD 19- CD 45- multiple myeloma (MM) cells (PhMCs) from a set of 54 bone marrow MM patient samples. And we found PhMCs contains a minor CD34+ fraction that possess myeloma-propagating activities in vitro and in vivo, as well as resistance to anticancer drugs. The percent of CD34+ PhMCs was significantly higher in relapse/refractory than in newly diagnosed samples. Gene expression profiling revealed that CD34- PhMCs had a general myeloma cell signature, whereas CD34+ PhMCs exhibited a more immature pre-germinal center like signature.
The presence of e cancer stem cells in MM was proposed for a few decades, however the identity of these cells remains controversial. The identification of these MM propagating cells provides a basis for better understanding the pathogenesis of MM and for designing novel therapeutic strategies aimed to eradicate total MM cells.

Academic Significance and Societal Importance of the Research Achievements

骨髄腫における幹細胞は、2,30年来その存在が提唱されてきたが、未だその実体については議論が分かれている。骨髄腫の起源となる細胞の同定は、骨髄腫のより詳細な病態解明だけでなく、骨髄腫根絶に向けた新たな治療戦略を構築する上で有用な基盤となる。

Research Products

• [Journal Article] Classic Hodgkin Lymphoproliferative Diseases Clonally Unrelated to B-Chronic Lymphocytic Leukemia Successfully Treated with Bendamustine Plus Rituximab. (2018)
  • Author(s): Rai S, Tanaka H, Fujimoto K, Kumode T, Inoue H, Taniguchi Y, Morita Y, Espinoza JL, Tatsumi Y, Ashida T, Matsuoka R, Kikuti YY, Nakamura N, Matsumura I.
  • Journal Title: Cancers (Basel). Volume: 10 Issue: 9 Pages: 304-304
  • DOI: 10.3390/cancers10090304
  • NAID: 120007133039
  • Peer Reviewed / Open Access
• [Journal Article] Pomalidomide with or without dexamethasone for relapsed/refractory multiple myeloma in Japan: a retrospective analysis by the Kansai Myeloma Forum (2018)
  • Author(s): Matsumura-Kimoto Y, Kuroda J, Kaneko H, Kamitsuji Y, Fuchida SI, Nakaya A, Shibayama H, Uoshima N, Yokota I, Uchiyama H, Yagi H, Kosugi S, Matsui T, Ishikawa J, Matsuda M, Ohta K, Iida M, Tanaka H, Kobayashi M, Wada K, Shimazaki C, Nomura S, Imada K, Hino M, Matsumura I, Kanakura Y, Takaori-Kondo A; KMF
  • Journal Title: International Journal of Hematology Volume: 107 Issue: 5 Pages: 541-550
  • DOI: 10.1007/s12185-018-2416-4
  • Peer Reviewed / Open Access
• [Journal Article] Retrospective analysis of primary plasma cell leukemia in Kansai Myeloma Forum registry (2018)
  • Author(s): Nakaya A, Yagi H, Kaneko H, Kosugi S, Kida T, Adachi Y, Shibayama H, Kohara T, Kamitsuji Y, Fuchida SI, Uoshima N, Kawata E, Uchiyama H, Shimura Y, Takahashi T, Urase F, Ohta K, Hamada T, Miyamoto K, Kobayashi M, Shindo M, Tanaka H, Shimazaki C, Hino M, Kuroda J, Kanakura Y, Takaoari-Kondo A, Nomura S, Matsumura I
  • Journal Title: Leukemia Research Reports Volume: 10 Pages: 7-10
  • DOI: 10.1016/j.lrr.2018.07.001
  • Peer Reviewed / Open Access
• [Journal Article] Immunemodulatory Effects of 5-Azacitidin Through Expansion of Functional Regulatory T Cells on Paraneoplastic Inflammation Associated With Myelodysplastic Syndromes: A Case Report (2018)
  • Author(s): Serizawa Kentaro、Tanaka Hirokazu、Morita Yasuyoshi、Taniguchi Takahide、Ashida Takashi、Matsumura Itaru
  • Journal Title: Frontiers in Oncology Volume: 8 Pages: 204-204
  • DOI: 10.3389/fonc.2018.00204
  • Peer Reviewed / Open Access
• [Journal Article] Gastric microbiota: An emerging player in Helicobacter pylori -induced gastric malignancies (2018)
  • Author(s): Espinoza JL, Matsumoto A, Tanaka H, Matsumura I.
  • Journal Title: Cancer Lett. Volume: 414 Pages: 147-152
  • DOI: 10.1016/j.canlet.2017.11.009
  • Peer Reviewed / Open Access
• [Journal Article] Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia. (2017)
  • Author(s): Togasaki E, Takeda J, Yoshida K, Shiozawa Y, Takeuchi M, Kiyoi H, Ohnishi K, Ohtake S, Asou N, Kobayashi Y, Miyazaki Y, Miyano S, Ogawa S, Matsumura I, Nakaseko C, Naoe T.
  • Journal Title: Blood Cancer J. Volume: 7 Issue: 4 Pages: 2017-2017
  • DOI: 10.1038/bcj.2017.36
  • Peer Reviewed / Open Access
• [Journal Article] Elevated plasma levels of procoagulant microparticles are a novel risk factor for thrombosis in patients with myeloproliferative neoplasms (2017)
  • Author(s): Taniguchi Yasuhiro、Tanaka Hirokazu、Luis Espinoza J.、Sakai Kazuko、Kumode Takahiro、Sano Keigo、Serizawa Kentarou、Rai Shinya、Morita Yasuyoshi、Hanamoto Hitoshi、Tsubaki Kazuo、Nishio Kazuto、Matsumura Itaru
  • Journal Title: Int J Hematol. Volume: 106 Issue: 5 Pages: 691-703
  • DOI: 10.1007/s12185-017-2302-5
  • Peer Reviewed / Open Access
• [Journal Article] Second primary malignancies among patients with myeloma-related-diseases in the KMF database (2016)
  • Author(s): Kosugi S, Shibayama H, Nakatani E, Kida T, Ohta K, Kaneko H, Yagi H, Tanaka H, Fuchida S, Nakaya A, Kobayashi M, Kuroda J, Kamitsuji Y, Uoshima N, Adachi Y, Tsudo M, Shimazaki C, Nomura S, Hino M, Matsumura I, Taniwaki M, Kanakura Y, Takaori-Kondo A.
  • Journal Title: Rinsho Ketsueki Volume: 57 Issue: 7 Pages: 839-847
  • DOI: 10.11406/rinketsu.57.839
  • NAID: 130005254870
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed / Open Access
• [Journal Article] ESAM is a novel human hematopoietic stem cell marker associated with a subset of human leukemias. (2016)
  • Author(s): Ishibashi T, Yokota T, Tanaka H, Ichii M, Sudo T, Satoh Y, Doi Y, Ueda T, Tanimura A, Hamanaka Y, Ezoe S, Shibayama H, Oritani K, Kanakura Y.
  • Journal Title: Experimental Hematology Volume: 44 Issue: 4 Pages: 269-281
  • DOI: 10.1016/j.exphem.2015.12.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] In vitro safety and efficacy of S888711, a novel thrombopoietin receptor agonist, in Myelodysplastic syndrome (2018)
  • Author(s): Keigo Sano, Hirokazu Tanaka, Itaru Matsumura
  • Organizer: 第1回国際がん研究シンポジウム
  • Int'l Joint Research
• [Presentation] 症候性骨髄腫1414例の後方視的解析：関西骨髄腫フォーラムからの最新報告 (2018)
  • Author(s): 田中 宏和, 芹澤 憲太郎, 中谷 綾, 金子 仁臣, 太田 健介, 小杉 智, 八木 秀男, 花本 仁, 淵田 真一, 志村 勇司, 柴山 浩彦, 小原 尚恵, 中谷 英仁, 諫田 淳也, 魚嶋 伸彦, 和田 勝也, 烏野 隆博, 松井 利充, 内山 人二, 松田 光弘, 足立 陽子, 高折 晃史, 黒田 純也, 谷脇 雅史, 島崎 千尋, 日野 雅之, 今田 和典, 野村 昌作, 金倉 譲, 松村 到
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 多発性骨髄腫治療におけるマルチカラー・フローサイトメトリーの有用性 ～MRD・微小環境の変動～ (2018)
  • Author(s): 田中 宏和
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 異常なRTKの細胞内輸送阻害は急性骨髄性白血病における有望な治療標的である。 (2018)
  • Author(s): 頼 晋也 田中 宏和, 鈴木 麻衣, Luis Espinoza, 谷村 朗, 森田 泰慶, 辰巳 陽一, 横田 貴史, 織谷 健司, 渡邊 俊雄, 金倉 譲, 松村 到
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] CD34陽性ヒト骨髄腫幹細胞の同定と特性解析 (2018)
  • Author(s): 芹澤 憲太郎, 田中 宏和, 福井 彩乃, 藤原 亮介, 佐野 圭吾, 口分田 貴裕, 谷口 康博, 森田 泰慶, ルイス エスピノザ, 辰巳 陽一, 芦田 隆司, 松村 到
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] BCR-ABL陰性骨髄増殖性腫瘍においてTET2変異は生存に対する予後不良因子である (2018)
  • Author(s): 谷口 康博, 田中 宏和, 藤原 亮介, 森田 泰慶, 花本 仁, 辰巳 陽一, 芦田 隆司, 松村 到
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] CLEC-2の発現は巨核球にバイアスした長期骨髄再建能を有する造血幹細胞集団を規定する (2018)
  • Author(s): 口分田 貴裕, 田中 宏和, J. Luis Espinoza, 岩田 吉生, 佐野 圭吾, 芹澤 憲太郎, 谷口 康博, 頼 晋也, 森田 泰慶, 辰巳 陽一, 芦田 隆司, 松村 到
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] In vitro safety and efficacy of S888711, a novel thrombopoietin receptor agonist, in Myelodysplastic syndrome (2018)
  • Author(s): Keigo Sano, Hirokazu Tanaka, Itaru Matsumura
  • Organizer: 第1回国際がん研究シンポジウム2018
  • Int'l Joint Research
• [Presentation] Identification of a patients-derived cd34+ myeloma cell population with tumor-propagating capacity and resistance to anticancer drugs (2017)
  • Author(s): Kentaro Serizawa, Hirokazu Tanaka, Ayano Fukui, Ryosuke Fujiwara, Keigo Sano, Hiroaki Inoue, Takahiro Kumode, Yasuhiro Taniguchi, Yasuyoshi Morita, Luis Espinoza, Itaru Matsumura
  • Organizer: 59th ASH Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] C-type lectin-like peceptor 2 specifies a finctionally distinct subpopulation of megakaryocyte-biased long-term hematopoietic stem cells. (2017)
  • Author(s): Takahiro Kumode, Hirokazu Tanaka, Ryosuke Fujiwara, Keigo Sano, Kentaro Serizawa, Yasuhiro Taniguchi, Sinya Rai, Itaru Matsumura
  • Organizer: 第22回欧州血液学会
  • Int'l Joint Research
• [Presentation] Azacitidine for patients with low-risk MDS after organ transplantation: a report of two cases (2016)
  • Author(s): Hiroaki Inoue, Yasuyoshi Morita, Shinya Rai, Hiroaki Kakutani, Yasuyo Ohyama, Yasuhiro Taniguchi, Hirokazu Tanaka, Takahiro Shimada, Yoichi Tatsumi, Takashi Ashida, Itaru Matsumura
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: 横浜市 パシフィコ横浜
  • Year and Date: 2016-10-13
• [Presentation] Procoagulant microparticle is a new surrogate biomarker for thrombotic events in patients with myeloproliferative neoplasms. (2016)
  • Author(s): Yasuhiro Taniguchi,Hirokazu Tanaka,Takahiro Kumode,Shinya Rai,Itaru Matsumura
  • Organizer: 第21回欧州血液学会
  • Place of Presentation: コペンハーゲン・デンマーク
  • Year and Date: 2016-06-09
  • Int'l Joint Research
• [Presentation] CLEC-2 EXPRESSION IS A NEW MARKER FOR A SUBSET OF HEMATOPOIETIC STEM/PROGENITOR CELLS THAT CONTRIBUTES TO INFLAMMATION-INDUCED EMERGENT MEGAKARYOPOIESIS (2016)
  • Author(s): Takahiro Kumode,Hirokazu Tanaka,Shinya Rai,Yasuhiro Taniguchi,Itaru Matsumura
  • Organizer: 第21回欧州血液学会
  • Place of Presentation: コペンハーゲン・デンマーク
  • Year and Date: 2016-06-09
  • Int'l Joint Research
• [Presentation] 多発性骨髄腫のpoor mobilizerに対するplerixafor併用下でのPBSCH (2016)
  • Author(s): 芹澤憲太郎、森田泰慶、口分田貴裕、田中宏和、山田枝里佳、芦田隆司、松村 到
  • Organizer: 第64回日本輸血・細胞治療学会
  • Place of Presentation: 京都市 国立京都国際会館
  • Year and Date: 2016-04-28