Suppression of tumor progression in multiple myeloma by osteogenic microenvironment: Elucidation of the molecular pathogenesis of tumor suppressing niche

• Project/Area Number: 21K16244
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: The University of Tokushima
• Principal Investigator: FUJII Shiro 徳島大学, 病院, 講師 (00618473)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2022: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 多発性骨髄腫 / 微小環境 / 細胞外小胞 / miRNA / 骨髄間質細胞 / 骨芽細胞 / 骨形成 / アポトーシス / PIM2

Outline of Research at the Start

骨髄腫細胞の生存・増殖を正から負へと変化させる因子として、骨芽細胞が産生し、骨基質小胞に包含、放出されるmiR-125bに着目し、miR-125bが骨髄腫細胞の生存・増殖の調節因子であるIRF4やその下流にあるPIM2の発現を抑制し、その結果もたらされるエネルギー産生や脂質や核酸などのバイオマスの産生や代謝経路への影響を明らかにする。解糖系やミトコンドリア生成、活性化の調節因子であるPGC-1α-AMPKシグナルの制御の破綻が細胞死を誘導すること、この代謝系のクライシスが現有の抗腫瘍薬への感受性を回復させることを示す。また、骨形成の誘導が骨髄腫に腫瘍排他的ニッチをも誘導することを立証する。

Outline of Final Research Achievements

Multiple myeloma（MM）is an incurable hematopoietic malignancy which has an affinity for bone. MM develops exclusively in the bone marrow and generates destructive bone disease. While the bone formation was suppressed in the MM bone marrow environment, inverse correlation between the tumor suppressive effects and osteogenesis has been shown in MM patients with responder of novel agents such as proteasome inhibitors. In the present study, co-culture of MM cells with mature osteoblasts which were differentiated from bone marrow stromal cells induced MM cell death different from co-culture with MC3T3-El pre-osteoblasts. We also found that the reduction of IL-6 expression, the increase of osteoprotegerin and miR-125b were shown in mature osteoblasts derived from pre-osteoblasts which conferred to MM cell death.

Academic Significance and Societal Importance of the Research Achievements

骨髄腫細胞は骨芽細胞分化を抑制に自らの生存・増殖に好適な骨髄微小環境を形成していること、そして骨形成誘導により骨髄腫細胞の生存を許容しない排他的ニッチが形成され、骨量の回復と共に抗腫瘍活性を高める可能性が示唆された。骨芽細胞分化を基軸に骨髄腫骨髄微小環境内での各種細胞間でのmiRの移動や骨髄腫細胞の代謝制御が明らかになると新たな治療概念、治療戦略の構築に寄与すると考えられる。

Research Products

• [Journal Article] A Genome-Wide Association Study Predicts the Onset of Dysgeusia Due to Anti-cancer Drug Treatment (2022)
  • Author(s): Takei M, Okada N, Nakamura S, Kagawa K, Fujii S, Miki H, Ishizawa K, Abe M, Sato Y.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 45 Issue: 1 Pages: 114-117
  • DOI: 10.1248/bpb.b21-00745
  • NAID: 130008139002
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2022-01-01
  • Peer Reviewed / Open Access
• [Journal Article] The importance of retaining physical functions to prevent skeletal-related events in multiple myeloma patients with bone disease (2022)
  • Author(s): Hirokazu Miki,Shingen Nakamura,Masahiro Oura,Masafumi Nakamura,Ryohei Sumitani,Kimiko Sogabe,Mamiko Takahashi,Tomoko Maruhashi,Takeshi Harada,Shiro Fujii,Hirofumi Hamano,Masateru Kondo,Naoto Okada,Itsuro Endo,Masahiro Abe
  • Journal Title: eJHaem Volume: － Issue: 2 Pages: 480-483
  • DOI: 10.1002/jha2.402
  • Peer Reviewed / Open Access
• [Journal Article] Retrospective Analysis of Autologous Stem Cell Transplantation for AL Amyloidosis: A Study from the Multiple Myeloma Working Group of the Japan Society for Hematopoietic Cell Transplantation (2022)
  • Author(s): Fuchida Shin-ichi、Kawamura Koji、Sunami Kazutaka、Tsukada Nobuhiro、Fujii Shiro、Ohkawara Hiroshi、Usuki Kensuke、Wake Atsushi、Endo Shinya、Ishiyama Ken、Ueda Yasunori、Nakamura Yukinori、Miyamoto Toshihiro、Fukuda Takahiro、Ichinohe Tatsuo、Atsuta Yoshiko、Takamatsu Hiroyuki
  • Journal Title: Transplantation and Cellular Therapy Volume: 28 Issue: 2 Pages: 76-82
  • DOI: 10.1016/j.jtct.2021.10.021
  • Peer Reviewed / Open Access
• [Journal Article] Acute Myeloid Leukemia Developing with Acute Pancreatitis Mimicking Autoimmune Pancreatitis (2021)
  • Author(s): Sumitani Ryohei、Hori Taiki、Murai Jumpei、Kawata Shiyori、Oura Masahiro、Sogabe Kimiko、Takahashi Mamiko、Harada Takeshi、Fujii Shiro、Miki Hirokazu、Kagawa Kumiko、Abe Masahiro、Nakamura Shingen
  • Journal Title: Internal Medicine Volume: 60 Issue: 11 Pages: 1753-1757
  • DOI: 10.2169/internalmedicine.4916-20
  • NAID: 130008046806
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-06-01
  • Peer Reviewed / Open Access
• [Journal Article] Allogeneic haematopoietic stem cell transplantation?clinical outcomes: impact of leg muscle strength (2021)
  • Author(s): Kondo Shin、Kagawa Kumiko、Saito Takashi、Oura Masahiro、Sogabe Kimiko、Harada Takeshi、Fujii Shiro、Nakamura Shingen、Miki Hirokazu、Sato Nori、Ono Rei、Abe Masahiro、Katoh Shinsuke
  • Journal Title: BMJ Supportive & Palliative Care Volume: 1 Pages: 003256-003256
  • DOI: 10.1136/bmjspcare-2021-003256
  • Peer Reviewed / Open Access
• [Journal Article] Intravenous busulfan-based conditioning with autologous stem cell transplantation for refractory B-cell lymphoma with central nervous system involvement (2021)
  • Author(s): Takahashi Mamiko、Sumitani Ryohei、Hori Taiki、Murai Jumpei、Kawata Shiyori、Oura Masahiro、Sogabe Kimiko、Harada Takeshi、Fujii Shiro、Miki Hirokazu、Kagawa Kumiko、Abe Masahiro、Nakamura Shingen
  • Journal Title: The Journal of Medical Investigation Volume: 68 Issue: 1.2 Pages: 196-201
  • DOI: 10.2152/jmi.68.196
  • NAID: 130008038399
  • Peer Reviewed / Open Access
• [Presentation] Local hyperthermia against extramedullary plasmacytomas: cooperation with proteasome inhibitors. (2022)
  • Author(s): Tomoko Maruhashi, Hirokazu Miki, Kimiko Sogabe, Asuka Oda, Masafumi Nakamura, Ryohei Sumitani, Masahiro Oura, Mamiko Takahashi, Takeshi Harada, Shiro Fujii, Shingen Nakamura, Masahiro Abe
  • Organizer: The 84th Annual Meeting of the Japanese Society of Hematology.
• [Presentation] 肝臓アミロイドーシスに対する超音波エラストグラフィを用いた非侵襲的診断法の有用性. (2022)
  • Author(s): 三木浩和, 中村信元, 中村昌史, 住谷龍平, 大浦雅博, 曽我部公子, 髙橋 真美子, 丸橋朋子, 原田武志, 藤井志朗, 西尾進, 友成哲, 安倍正博
  • Organizer: 第47回日本骨髄腫学会学術集会
• [Presentation] 形質細胞疾患における新型コロナワクチンの有効性 (2022)
  • Author(s): 中村信元, 堀太貴, 中村昌史, 住谷龍平, 大浦雅博, 曽我部公子, 丸橋朋子, 髙橋真美子, 藤井志朗, 三木浩和, 原田武志, 安倍正博
  • Organizer: 第47回日本骨髄腫学会学術集会
• [Presentation] RNA編集酵素ADAR1を標的にする1q増幅骨髄腫細胞に対する治療法の開発 (2022)
  • Author(s): 原田武志, 住谷龍平, 小田明日香, 井上雄介, 大浦雅博, 曽我部公子, 丸橋朋子, 高橋真美子, 藤井志朗, 中村信元, 三木浩和, 天眞寛文, 日浅雅博, 寺町順平, 安倍正博
  • Organizer: 第47回日本骨髄腫学会学術集会
• [Presentation] 骨髄腫細胞のプロテアソーム阻害薬への抵抗性の機序と温熱療法によるその克服の可能性 (2022)
  • Author(s): 丸橋 朋子, 三木 浩和, 曽我部 公子, 原田 武志, 小田 明日香, 中村 信元, 中村 昌史,住谷 龍平, 大浦 雅博, 高橋 真美子, 藤井志朗, 安倍 正博
  • Organizer: 第47回日本骨髄腫学会学術集会
• [Presentation] 骨髄腫に対する抗体免疫療法へのTh1様γδT細胞の応用 (2022)
  • Author(s): 井上雄介, 原田武志, 天眞寛文, 小田明日香, 住谷龍平, 大浦雅博, 曽我部公子, 丸橋朋子, 高橋真美子, 藤井志朗, 中村信元, 三木浩和, 日浅雅博, 寺町順平, 安倍正博
  • Organizer: 第47回日本骨髄腫学会学術集会
• [Presentation] TAK1 阻害は骨髄腫の細胞間相互作用による骨破壊と薬剤耐性を改善する (2022)
  • Author(s): 寺町順平, 天真寛文, 日浅雅博, 小田明日香, 清水宗, 住谷龍平, 大浦雅博, 曽我部公子, 丸橋朋子, 藤井志朗, 中村信元, 三木浩和, 遠藤逸朗, 原田 武志, 安倍正博
  • Organizer: 第47回日本骨髄腫学会学術集会
• [Presentation] Down-regulation of the IRF4-SLAMF7 axis in MM cells by CELMoDs and HDAC inhibition. (2021)
  • Author(s): Yusuke Inoue, Takeshi Harada, Hirofumi Tenshin, Asuka Oda, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Shiro Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Masahiro Hiasa, Jumpei Teramachi, Masahiro Abe
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Resumption of myeloma cell sensitivity to proteasome inhibitors by PIM and Akt inhibition (2021)
  • Author(s): Kimiko Sogabe, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Asuka Oda, Yusuke Inoue, Ryohei Sumitani, Tomoko Maruhashi, Masahiro Oura, Shiro Fujii, Kumiko Kagawa, Hirofumi Tenshin, Masahiro Hiasa, Jumpei Teramachi, Masahiro Abe
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Diagnostic efficacy of non-invasive ultrasound shear wave elastography for hepatic AL amyloidosis. (2021)
  • Author(s): Hirokazu Miki, Shingen Nakamura, Shiro Fujii, Masafumi Nakamura, Makiko Mizuguchi, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Mamiko Takahashi, Tomoko Maruhashi, Takeshi Harada, Kumiko Kagawa, Susumu Nishio, Tetsu Tomonari, Masahiro Abe
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Expansion of γδ T cells by CELMoDs and enhancement of their anti-myeloma effects by elotuzumab. (2021)
  • Author(s): Takeshi Harada, Yusuke Inoue, Hirofumi Tenshin, Asuka Oda, Rhohei Sumitani, Masahiro Oura, Kimiko Sogabe, Shiro Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Masahiro Hiasa, Jumpei Teramachi, Masahiro Abe
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Induction of elotuzumab’s ADCC activity by Th1-like γδ T cells towards osteoclasts as well as myeloma cells. (2021)
  • Author(s): Takeshi Harada, Yusuke Inoue, Hirofumi Tenshin, Asuka Oda, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Shiro Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Masahiro Hiasa, Jumpei Teramachi, Masahiro Abe
  • Organizer: EH2021 26th Congress of European Hematology Association
• [Presentation] Mechanisms for the resistance to proteasome inhibitors in myeloma cells: the role of PIM2 and Akt kinase activation and NRF2 accumulation (2021)
  • Author(s): Kimiko Sogabe Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Asuka Oda, Yusuke Inoue, Ryohei Sumitani, Masahiro Oura, Shiro Fujii, Kumiko Kagawa, Hirofumi Tenshin, Jumpei Teramachi, Masaki Ri, Shinsuke Iida, Masahiro Abe
  • Organizer: 第46回日本骨髄腫学会学術集会
• [Presentation] Development of combinatory treatment of Th1-like γδ T cells with elotuzumab against osteoclasts as well as myeloma cells. (2021)
  • Author(s): Takeshi Harada, Yusuke Inoue, Hirofumi Tenshin, Asuka Oda, Rhohei Sumitani, Masahiro Oura, Kimiko Sogabe, Shiro Fujii, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Masahiro Hiasa, Jumpei Teramachi, Masahiro Abe
  • Organizer: 第46回日本骨髄腫学会学術集会
• [Presentation] The importance of retaining physical functions to prevent SRE in multiple myeloma. (2021)
  • Author(s): Hirokazu Miki, Shingen Nakamura, Masafumi Nakamura, Makiko Mizuguchi, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Mamiko Takahashi, Tomoko Maruhashi, Takeshi Harada, Shiro Fujii, Kumiko Kagawa, Hirofumi Hamano, Masateru Kondo, Naoto Okada, Yoshimi Bando, Itsuro Endo, Masahiro Abe
  • Organizer: 第46回日本骨髄腫学会学術集会
• [Presentation] The importance of retaining physical functions to prevent skeletal-related events in multiple myeloma patients with bone disease. (2021)
  • Author(s): Hirokazu Miki, Shingen Nakamura, Masafumi Nakamura, Makiko Mizuguchi, Ryohei Sumitani, Masahiro Oura, Kimiko Sogabe, Mamiko Takahashi, Tomoko Maruhashi, Takeshi Harada, Shiro Fujii, Kumiko Kagawa, Hirofumi Hamano, Masateru Kondou, Naoto Okada, Yoshimi Bando, Itsuro Endo, Masahiro Abe
  • Organizer: The 48th annual meeting of European Calcified Tissue Society (ECTS)