Investigation of molecular mechanism by which PBK contributes to tumorigenesis in myeloma cells

• Project/Area Number: 18K08342
• 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: Aichi Medical University
• Principal Investigator: Ota Akinobu 愛知医科大学, 医学部, 講師 (30438048)
• Co-Investigator(Kenkyū-buntansha): 武井 則雄 北海道大学, 医学研究院, 助教 (50523461) ; 花村 一朗 愛知医科大学, 医学部, 教授 (70440740)
• Project Period (FY): 2018-04-01 – 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 多発性骨髄腫 / 分子標的薬 / キナーゼ / 造腫瘍性 / PBK / 治療薬 / 分子病態 / トランスレーショナルリサーチ / ノックアウトマウス / 悪性化 / 治療 / マウス / ゲノム編集 / 治療標的分子

Outline of Final Research Achievements

Multiple myeloma (MM) is a complex plasma cell neoplasm, accounting for approximately 10% of all hematological malignancies. Novel molecular-targeted therapy based on their genomic abnormalities in the patients with MM is really wanted to improve their clinical outcome. In this study, we identified that interleukin-6 readily increases PBK expression. Kaplan-Meier analysis showed that the MM patients with higher expression of PBK have a significant shorter survival time compared with those with moderate/lower expression of PBK. Knockout of PBK dramatically suppressed in vivo tumor growth in MM cells. Mechanistically, loss of PBK increased the number of apoptotic cells with concomitant decrease in the phosphorylation level of Stat3. A novel PBK inhibitor OTS514 significantly decreased KMS-11-derived tumor growth. These findings highlight the novel oncogenic role of PBK in tumor growth of myeloma, and it might be a novel therapeutic target for the treatment of patients with MM.

Academic Significance and Societal Importance of the Research Achievements

本研究は、多発性骨髄腫（以下MM）の発症から悪性化に至る過程に関わる分子機構の解明を目指して行われた。MMは、血液細胞の１種である形質細胞の異常が原因となって起こる。MM細胞はインターロイキン6（IL-6）によって生存・増殖がサポートされる。代表者はこの点に着目して、IL-6の刺激がMM細胞に与える影響を解析した結果、リン酸化酵素PBKの発見に至った。また、PBKの遺伝子量が多いMM患者の生存率は有意に低下すること、PBK遺伝子の欠失はMM腫瘍増殖能の低下をきたすことを発見した。本研究結果は、PBKを標的とした難治性MMに対する新たな分子病態を明らかとしたもので、創薬につながる可能性が高い。

Research Products

• [Int'l Joint Research] University of Washington(米国)
• [Journal Article] Chromosomal translocation t(11;14) and p53 deletion induced by the CRISPR/Cas9 system in normal B cell-derived iPS cells (2021)
  • Author(s): Yusuke Azami, Naohiro Tsuyama, Yu Abe, Misaki Sugai-Takahashi, Ken-Ichi Kudo, Akinobu Ota, Karnan Sivasundaram , Moe Muramatsu, Tomonari Shigemura, Megumi Sasatani, Yuko Hashimoto, Shigehira Saji, Kenji Kamiya, Ichiro Hanamura, Takayuki Ikezoe, Masafumi Onodera, Akira Sakai.
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 5216-5216
  • DOI: 10.1038/s41598-021-84628-5
  • Peer Reviewed / Open Access
• [Journal Article] PBK expression predicts favorable survival in colorectal cancer patients (2021)
  • Author(s): Nagano-Matsuo A, Inoue S, Koshino A, Ota A, Nakao K, Komura M, Kato H, Naiki-Ito A, Watanabe K, Nagayasu Y, Hosokawa Y, Takiguchi S, Kasugai K, Kasai K, Inaguma S, Takahashi S
  • Journal Title: Virchows Archiv Volume: - Issue: 2 Pages: 277-284
  • DOI: 10.1007/s00428-021-03062-0
  • Peer Reviewed / Open Access
• [Journal Article] Identification of CD24 as a potential diagnostic and therapeutic target for malignant pleural mesothelioma (2020)
  • Author(s): KarnanS, Ota A, Murakami H, Rahman ML, Hasan MN, Wahiduzzaman MD, Hanamura I, Vu LQ, Inoko A, Hyodo T, Konishi H, Tsuzuki S, Hosokawa Y.
  • Journal Title: Cell Death Discovery Volume: 18 Issue: 1 Pages: 127-139
  • DOI: 10.1038/s41420-020-00364-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of cisplatin-resistant factor by integration of transcriptomic and proteomic data using head and neck carcinoma cell lines (2020)
  • Author(s): Inukai D, Nishimura K, Okamoto H, Sano R, Ueda H, Ota A, Karnan S, Hosokawa Y, Yoshikawa K, Suzuki S, Ueda R, Murotani K, Bradford CR, Ogawa T
  • Journal Title: Nagoya Journal of Medical Science Volume: 82 Issue: 3 Pages: 519-531
  • DOI: 10.18999/nagjms.82.3.519
  • NAID: 120006881553
  • ISSN: 2186-3326
  • URL: https://nagoya.repo.nii.ac.jp/records/30422
  • Peer Reviewed / Open Access
• [Journal Article] Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells (2020)
  • Author(s): Ota Akinobu、Hanamura Ichiro、Karnan Sivasundaram、Inaguma Shingo、Takei Norio、Lam Vu Quang、Mizuno Shohei、Kanasugi Jo、Wahiduzzaman Md、Rahman Md Lutfur、Hyodo Toshinori、Konishi Hiroyuki、Tsuzuki Shinobu、Ikeda Hiroshi、Takami Akiyoshi、Hosokawa Yoshitaka
  • Journal Title: Journal of Interferon & Cytokine Research Volume: 40 Issue: 8 Pages: 389-405
  • DOI: 10.1089/jir.2020.0111
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interferon-γ-induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG-CoA reductase (2020)
  • Author(s): Maenaka A, Kenta I, Ota A, Miwa Y, Ohashi W, Horimi K, Matsuoka Y, Ohnishi M, Uchida K, Kobayashi T
  • Journal Title: FEBS Open Bio Volume: - Issue: 5 Pages: 927-936
  • DOI: 10.1002/2211-5463.12854
  • Peer Reviewed / Open Access
• [Journal Article] Bi-allelic loss of FAM46C triggers tumor growth with concomitant activation of Akt signaling in multiple myeloma cells (2020)
  • Author(s): Kanasugi J, Hanamura I, Ota A, Karnan S, Vu LQ, Mizuno S, Wahiduzzaman M, Rahman ML, Hyodo T, Konishi H, Tsuzuki S, Hosokawa Y, Takami A
  • Journal Title: Cancer Science Volume: - Issue: 5 Pages: 999-999
  • DOI: 10.1111/cas.14386
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Discovery of novel molecular characteristics and cellular biological properties in ameloblastoma (2020)
  • Author(s): Kondo Sayuri、Ota Akinobu、Ono Takayuki、Karnan Sivasundaram、Wahiduzzaman Md、Hyodo Toshinori、Lutfur Rahman Md、Ito Kunihiro、Furuhashi Akifumi、Hayashi Tomio、Konishi Hiroyuki、Tsuzuki Shinobu、Hosokawa Yoshitaka、Kazaoka Yoshiaki
  • Journal Title: Cancer Medicine Volume: 9 Issue: 8 Pages: 2904-2917
  • DOI: 10.1002/cam4.2931
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CRISPR-Casシステムを用いたゲノム編集と骨髄腫の新たな悪性化因子の同定 (2020)
  • Author(s): 太田明伸, 花村一朗, 細川好孝
  • Journal Title: Precision Medicine Volume: 3(6) Pages: 571-575
• [Journal Article] CRISPR-Casシステムを用いた骨髄腫の悪性化に関わる分子機構の解明 (2020)
  • Author(s): 太田明伸, 花村一朗, 細川好孝
  • Journal Title: Precision Medicine Volume: 4(1) Pages: 60-64
• [Journal Article] Novel mechanistic insights into the anti-cancer mode of arsenic trioxide (2020)
  • Author(s): Wahiduzzaman M, Ota A, Hosokawa Y.
  • Journal Title: Current Cancer Drug Targets Volume: 20(2) Issue: 2 Pages: 115-129
  • DOI: 10.2174/1568009619666191021122006
  • Peer Reviewed
• [Journal Article] Tandem paired nicking promotes precise genome editing with scarce interference by p53 (2019)
  • Author(s): Hyodo T, Rahman ML, Karnan S, Ito T, Toyoda A, Ota A, Wahiduzzaman M, Tsuzuki S, Okada Y, Hosokawa Y, Konishi H.
  • Journal Title: Cell Rep. Volume: 30 Issue: 4 Pages: 1195-1207
  • DOI: 10.1016/j.celrep.2019.12.064
  • Peer Reviewed / Open Access
• [Journal Article] 多発性骨髄腫の進展に関わる分子機構とPBKの関与 (2019)
  • Author(s): 太田 明伸, 花村 一朗
  • Journal Title: BIO Clinica Volume: 34(6) Pages: 86-92
• [Journal Article] ゲノム編集法を用いた骨髄腫の悪性化に関わる分子機構の解析 (2019)
  • Author(s): 太田 明伸, 細川好孝
  • Journal Title: Medical Science Digest Volume: 45(9) Pages: 8-11
• [Journal Article] 多発性骨髄腫におけるPBK 発現の意義と 治療標的としての可能性 (2019)
  • Author(s): 太田明伸，花村一朗，細川好孝
  • Journal Title: BIO Clinica Volume: 34(13) Pages: 65-69
• [Journal Article] Establishment of a mouse model for injury-induced scar formation and the accompanying chronic pain: Comprehensive microarray analysis of molecular expressions in fibrosis and hyperalgesia. (2019)
  • Author(s): Li Y, Iida H, Kimata K, Zhuo L, Ota A, Kimura S, Yin X, Deie M, Ushida T.
  • Journal Title: Molecular Pain Volume: - Pages: 174480691989238-174480691989238
  • DOI: 10.1177/1744806919892389
  • Peer Reviewed / Open Access
• [Journal Article] 多発性骨髄腫の進展に関わる分子機構とPBKの関与 (2019)
  • Author(s): 太田明伸、花村一朗
  • Journal Title: BIO Clinica Volume: 451 Pages: 86-92
  • Peer Reviewed
• [Journal Article] Establishment and characterization of CRISPR/Cas9-mediated NF2(-/-) human mesothelial cell line: Molecular insight into fibroblast growth factor receptor 2 in malignant pleural mesothelioma (2019)
  • Author(s): Wahiduzzaman Md、Karnan Sivasundaram、Ota Akinobu、Hanamura Ichiro、Murakami Hideki、Inoko Akihito、Rahman Md Lutfur、Hyodo Toshinori、Konishi Hiroyuki、Tsuzuki Shinobu、Hosokawa Yoshitaka
  • Journal Title: Cancer Science Volume: 110 Issue: 1 Pages: 180-193
  • DOI: 10.1111/cas.13871
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and characterization of a novel vincristine-resistant diffuse large B-cell lymphoma cell line containing the 8q24 homogeneously staining region (2018)
  • Author(s): Mizuno S、Hanamura I、Ota Akinobu、Karnan S、Kanasugi J、Nakamura A、Takasugi S、Uchino Ki、Horio T、Goto、Murakami S、Gotou M、Yamamoto H、Watarai M、Shikami M、Hosokawa Y、Miwa H、Taniwaki M、Ueda R、Nitta M、Takami A
  • Journal Title: FEBS Open Bio Volume: 8 Issue: 12 Pages: 1977-1991
  • DOI: 10.1002/2211-5463.12538
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The plant alkaloid conophylline inhibits matrix formation of fibroblasts (2018)
  • Author(s): Tezuka Takehiko、Ota Akinobu、Karnan Sivasundaram、Matsuura Katsuhiko、Yokoo Kazuhisa、Hosokawa Yoshitaka、Vigetti Davide、Passi Alberto、Hatano Sonoko、Umezawa Kazuo、Watanabe Hideto
  • Journal Title: Journal of Biological Chemistry Volume: 293 Issue: 52 Pages: 20214-20226
  • DOI: 10.1074/jbc.ra118.005783
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation of PTEN?knockout (-/-) murine prostate cancer cells using the CRISPR/Cas9 system and comprehensive gene expression profiling (2018)
  • Author(s): Takao Akiko、Yoshikawa Kazuhiro、Karnan Sivasundaram、Ota Akinobu、Uemura Hirotsugu、De Velasco Marco、Kura Yurie、Suzuki Susumu、Ueda Ryuzo、Nishino Tokiko、Hosokawa Yoshitaka
  • Journal Title: Oncology Reports Volume: 40 Pages: 2455-2466
  • DOI: 10.3892/or.2018.6683
  • Peer Reviewed
• [Journal Article] Novel combined Ato-C treatment synergistically suppresses proliferation of Bcr-Abl-positive leukemic cells in vitro and in vivo (2018)
  • Author(s): Wahiduzzaman Md、Ota Akinobu、Karnan Sivasundaram、Hanamura Ichiro、Mizuno Shohei、Kanasugi Jo、Rahman Md Lutfur、Hyodo Toshinori、Konishi Hiroyuki、Tsuzuki Shinobu、Takami Akiyoshi、Hosokawa Yoshitaka
  • Journal Title: Cancer Letters Volume: 433 Pages: 117-130
  • DOI: 10.1016/j.canlet.2018.06.027
  • Peer Reviewed
• [Journal Article] Inhibition of NADPH oxidase 2 induces apoptosis in osteosarcoma: The role of reactive oxygen species in cell proliferation (2018)
  • Author(s): Kitamoto Kazumasa、Miura Yuji、Karnan Sivasundaram、Ota Akinobu、Konishi Hiroyuki、Hosokawa Yoshitaka、Sato Keiji
  • Journal Title: Oncology Letters Volume: 15 Pages: 7955-7962
  • DOI: 10.3892/ol.2018.8291
  • Peer Reviewed / Open Access
• [Journal Article] Versican A-subdomain is required for its adequate function in dermal development. (2017)
  • Author(s): Hatano S, Nagai N, Sugiura N, Tsuchimoto J, Isogai z, Kimata K, Ota A, Karnan S, Hosokawa Y, Watanabe H
  • Journal Title: Connect Tissue Res Volume: 印刷中 Issue: 2 Pages: 178-190
  • DOI: 10.1080/03008207.2017.1324432
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 骨髄腫細胞におけるPBZ binding kinaseの腫瘍促進作用と治療標的分子としての可能性 (2019)
  • Author(s): 太田明伸、花村一朗、Karnan Sivasundaram、高見昭良、細川好孝
  • Organizer: 第44回日本骨髄腫学会学術総会
• [Presentation] Biallelic Loss of FAM46C Promotes the Proliferation of Multiple Myeloma Cells with Concomitant Upregulation of P13K-AKT Signaling (2019)
  • Author(s): Jo Kanasugi, Ichiro Hanamura, Akinobu Ota, Sivasundaram Karnan, Lam Quang Vu, Yoshitaka Hosokawa, Akiyoshi Takami
  • Organizer: 第10回日本血液学会（JSH）国際シンポジウム
• [Presentation] CRISPR/Cas9 nickase によるサイレント変異不要のノックイン (2019)
  • Author(s): 兵頭寿典、Md Lutfur Rahman、豊田敦、Sivasundaram Karnan、太田明伸、都築忍、 細川好孝、小西裕之
  • Organizer: 第4回日本ゲノム編集学会
• [Presentation] CRISPR/Cas9 nickaseによるノックインはp53を活性化しない (2019)
  • Author(s): 兵頭寿典、Md Lutfur Rahman、Sivasundaram Karnan、太田明伸、都築忍、細川好孝、 小西裕之
  • Organizer: 第4回日本ゲノム編集学会
• [Presentation] Experimental conditions permitting efficient targeted koock-in using CRISPR/Cas9 nickase (2019)
  • Author(s): Md Lutfur Rahman, Toshinori Hyodo, Sivasundaram Karnan, Akinobu Ota, Shinobu Tsuzuki, Yoshitaka Hosokawa, Hiroyuki Konishi
  • Organizer: 第4回日本ゲノム編集学会
• [Presentation] CRISPRCas9を用いたNF2及びCDKN2Aノックアウトヒト中皮腫細胞株の樹立と分子生物学的解析 (2019)
  • Author(s): Sivasundaram Karnan, Akinobu ota, Ichiro Hanamura, Hideki Murakami, Toshinori Hyodo, Wahiduzzanan Md, Hiroyuki Konishi , Shinobu Tsuzuki, Yoshitaka Hosokawa
  • Organizer: 第92回日本生化学会大会
• [Presentation] p16/NF2遺伝子の欠損により発現の誘導される悪性中皮腫特異的分子の同定 (2019)
  • Author(s): シバスンダラン カルナン、太田明伸、花村一朗、村上秀樹、兵頭寿典、小西裕之、 都築忍、細川好孝
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Chromosomal translocation t(11;14) and p53 deletion in B cell-derived iPS cells by CRISPR/Cas9 (2019)
  • Author(s): Aki Yanagi, Naohiro Tsuyama, Misaki Sugai, Yu Abe, Yukari Yanai, Akinobu Ota, Karnan Sivasundaram, Lobna Alkebsi, Moe Muramatsu, Tomonari Shigemura, Megumi Sasatani, Yuko Hashimoto, Kenji Kamiya, Ichiro Hanamura, Takayuki Ikezoe, Masafumi Onodera, Akira Sakai.
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Tandem paired nicking using Cas9 nickases permits targeted knock-in without significant inhibition by p53 (2019)
  • Author(s): Toshinori Hyodo, Md Lutfur Rahman, Atsushi Toyoda, Sivasundaram Karnan, Akinobu Ota, Shinobu Tuzuki, Yoshitaka Hosokawa, Hiroyuki Konishi
  • Organizer: Frontiers in Genome Engineering 2019
  • Int'l Joint Research
• [Presentation] DNA二重鎖切断を介さない変異ノックイン法（Targeted knock-in without introducing double-stranded DNA breaks） (2019)
  • Author(s): 兵頭寿典、Md Lutfur Rahman、豊田敦、Sivasundaram Karnan、太田明伸、都築忍、 細川好孝、小西裕之
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Introduction of Chromosomal Translocation t(11; 14) and a p53 Deletion into Normal B Cell-derived iPSCs to Elucidate the Cellular Origin of Myeloma Cells. (2019)
  • Author(s): Yanagi A, Tsuyama N, Sugai M, Abe Y, Azami Y, Yanai Y, Ota A, Sivasundaram K, Muramatsu M, Shigemura T, Sasatani M, Hashimot Y, Kamiya K, Hanamura I, Ikezoe T, Onodera M, Sakai A.
  • Organizer: 61th ASH Annual Meeting
  • Int'l Joint Research
• [Presentation] Identification of Genome-wide Molecular Characteristics in Ameloblastoma:Role of Tlr2 in Ameloblastoma Cells (2019)
  • Author(s): S.Kondo, A.Ota, T.Ono, S.Karnan, M.Wahiduzzaman, T.Hyodo, M.L.Rahman, K.Ito, A.Furuhashi, T.Hayashi, H.Konishi, S.Tuzuki, Y.Hosokawa, Y.Kazaoka
  • Organizer: ASCB/EMBO 2019 Meeting
  • Int'l Joint Research
• [Presentation] Role of PBK in multiple myeloma cell growth: implication of PBK in novel molecular targets for anti-myeloma therapy (2019)
  • Author(s): 太田明伸, 花村一朗, KARNAN Sivasundaram, 高見昭良, 細川好孝
  • Organizer: 第44回日本骨髄腫学会
• [Presentation] 骨髄腫細胞のレナリドマイド耐性に関連する付加的ゲノム異常と遺伝子発現変化の基礎的検討 (2018)
  • Author(s): 太田明伸, 花村一朗, KARNAN Sivasundaram, 高見昭良, 細川好孝
  • Organizer: 第43回日本骨髄腫学会
• [Presentation] 多発性骨髄腫の腫瘍増殖におけるPDZ binding kinaseの関与 (2018)
  • Author(s): 太田明伸、花村一朗、シバスンダラン カルナン、小西裕之、都築忍、細川好孝
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 悪性中皮腫細胞の増殖を特異的に抑制するAkt阻害剤の探索と同定 (2018)
  • Author(s): 太田明伸、山地 雅之、 ワヒドッジャマン ムハマド、シバスンダラン カルナン、 兵頭 寿典、小西 裕之、都築 忍、羽生田 正行、細川 好孝
  • Organizer: 第91回日本生化学会大会
• [Presentation] P16/NF2 遺伝子の欠損により発現の誘導される悪性中皮腫特異的分子の同定 (2018)
  • Author(s): シバスンダラン カルナン、太田明伸、花村一朗、村上秀樹、 ムハマド ワヒドッジャマン、兵頭寿典、小西裕之、都築忍、細川好孝
  • Organizer: 第77回日本癌学会学術総会
• [Book] Current Understanding of Apoptosis: Arsenic-Based Anticancer-Combined Therapy: Novel Mechanism Inducing Apoptosis of Cancer Cells (2018)
  • Author(s): Ota Akinobu、Wahiduzzaman Md、Hosokawa Yoshitaka
  • Total Pages: 22
  • Publisher: IntechOpen
  • ISBN: 9781789235012
• [Remarks] 多発性骨髄腫に対する新しい治療標的分子の発見！
  • URL: https://www.aichi-med-u.ac.jp/files/soumu/2020topics03.pdf