Induction of p53-dependent and -independent mitochondrial death based on the BCL-2 profile in hematological malignancies

• Project/Area Number: 17K09928
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kochi University (2019-2020); Saga University (2017-2018)
• Principal Investigator: KOJIMA KENSUKE 高知大学, 教育研究部医療学系臨床医学部門, 教授 (10332793)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 造血器腫瘍 / 分子標的治療 / BCL-2 / 薬剤耐性 / MCL-1 / p53 / 耐性 / シグナル伝達 / 細胞死

Outline of Final Research Achievements

We have found that malignant hematopoietic cells have their own anti-apoptotic adaptation program irrespective for p53 status and obtain resistance against molecular target drugs via changing cellular BCL-2 profile, not through the selection of cells with newly obtaining genetic abnormalities.

Academic Significance and Societal Importance of the Research Achievements

本研究により、腫瘍特異的な分子標的治療をおこなった際の治療耐性機序として、長期的に生存依存性を示すBCL-2ファミリー・プロファイルを変えてゆくことで、ゲノム異常によらずがん細胞が薬剤耐性を獲得することを、具体的な造血器腫瘍モデルとともに見いだした。腫瘍シグナル変化の解析をおこなったところ一部は p53シグナルに干渉するものであったことから、p53シグナル活性化治療との併用など、新たな分子標的治療戦略として発展につながる結果であった。

Research Products

• [Int'l Joint Research] MD Anderson Cancer Center(米国)
• [Int'l Joint Research] MD Anderson Cancer Center/PTC Therapeutics/Daiichi Sankyo Inc.(米国)
• [Int'l Joint Research] MD Anderson Cancer Center(米国)
• [Journal Article] Central Nervous System Involvement in Mantle Cell Lymphoma Presenting Magnetic Resonance Imaging Features of Mild Encephalitis/Encephalopathy with a Reversible Splenial Lesion (2021)
  • Author(s): Nakamura Makoto、Iwasa Hitomi、Kojima Kensuke
  • Journal Title: Internal Medicine Volume: 60 Issue: 10 Pages: 1597-1600
  • DOI: 10.2169/internalmedicine.6386-20
  • NAID: 130008038569
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-05-15
  • Peer Reviewed / Open Access
• [Journal Article] Prophylactic antiviral therapy for hepatitis B virus surface antigen‐positive patients with diffuse large B‐cell lymphoma treated with rituximab‐containing chemotherapy (2021)
  • Author(s): Yamauchi Nobuhiko、Maruyama Dai、Choi Ilseung、Atsuta Yoshiko、Sakai Rika、Miyashita Kazuho、Moriuchi Yukiyoshi、Tsujimura Hideki、Kubota Nobuko、Yamamoto Go、Igarashi Tadahiko、Izutsu Koji、Yoshida Shinichiro、Kojima Kensuke、・・・、Kusumoto Shigeru
  • Journal Title: Cancer Science Volume: 112 Issue: 5 Pages: 1943-1954
  • DOI: 10.1111/cas.14846
  • Peer Reviewed / Open Access
• [Journal Article] Chronic myeloid leukemia with variant e13a3 (b2a3) <i>BCR-ABL1</i> as an ABL1 tyrosine kinase inhibitor-sensitive subtype (2021)
  • Author(s): 砥谷 和人、朝霧 正、上岡 樹生、小島 研介
  • Journal Title: Rinsho Ketsueki Volume: 62 Issue: 3 Pages: 180-185
  • DOI: 10.11406/rinketsu.62.180
  • NAID: 130008022236
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Acquired hypofibrinogenemia in patients with leukemia during steroid therapy (2021)
  • Author(s): 小笠原史也、 伊藤孟彦、中村 真、佐伯恭昌、谷口亜裕子、 砥谷和人、小島研介
  • Journal Title: Rinsho Ketsueki Volume: 62 Issue: 3 Pages: 193-195
  • DOI: 10.11406/rinketsu.62.193
  • NAID: 130008022252
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Targeting aberrant DNA hypermethylation as a driver of ATL leukemogenesis by using the new oral demethylating agent OR-2100 (2020)
  • Author(s): Watanabe Tatsuro、Yamashita Satoshi、Ureshino Hiroshi、Kamachi Kazuharu、Kurahashi Yuki、Fukuda-Kurahashi Yuki、Yoshida Nao、Hattori Naoko、Nakamura Hideaki、Sato Akemi、Kawaguchi Atsushi、Sueoka-Aragane Naoko、Kojima Kensuke、Okada Seiji、Ushijima Toshikazu、Kimura Shinya、Sueoka Eisaburo
  • Journal Title: Blood Volume: 136 Issue: 7 Pages: 871-884
  • DOI: 10.1182/blood.2019003084
  • Peer Reviewed / Open Access
• [Journal Article] Treatment algorithm for Japanese patients with chronic lymphocytic leukemia in the era of novel targeted therapies (2020)
  • Author(s): Kojima Kensuke、Burger Jan A.
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 60 Issue: 4 Pages: 130-137
  • DOI: 10.3960/jslrt.20002
  • NAID: 130007955989
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Primary pulmonary diffuse large B cell lymphoma presenting as bulky bilateral lung tumors (2020)
  • Author(s): Saeki Kyosuke、Nakamura Makoto、Egashira Ryoko、Kojima Kensuke
  • Journal Title: Annals of Hematology Volume: 100 Issue: 2 Pages: 577-578
  • DOI: 10.1007/s00277-020-04040-3
  • Peer Reviewed
• [Journal Article] Gastric emphysema in chemosensitive gastric diffuse large B cell lymphoma (2020)
  • Author(s): Nakamura Makoto、Saeki Kyosuke、Egashira Ryoko、Egashira Yoshiaki、Kojima Kensuke
  • Journal Title: Annals of Hematology Volume: 99 Issue: 10 Pages: 2457-2458
  • DOI: 10.1007/s00277-020-04118-y
  • Peer Reviewed
• [Journal Article] Treatment strategies for chronic lymphocytic leukemia in the era of novel targeted therapies (2020)
  • Author(s): 小島 研介
  • Journal Title: Rinsho Ketsueki Volume: 61 Issue: 9 Pages: 1275-1280
  • DOI: 10.11406/rinketsu.61.1275
  • NAID: 130007937063
  • ISSN: 0485-1439, 1882-0824
• [Journal Article] Clinical impact of the CONUT score in patients with multiple myeloma (2020)
  • Author(s): Okamoto S, Ureshino H*, Kidoguchi K, Kusaba K, Kizuka-Sano H, Sano H, Nishioka A, Yamaguchi K, Kamachi K, Itamura H, Yoshimura M, Yokoo M, Shindo T, Kubota Y, Ando T, Kojima K, Kawaguchi A, Sueoka E, Kimura S.
  • Journal Title: Ann Hematol Volume: 99 Issue: 1 Pages: 113-119
  • DOI: 10.1007/s00277-019-03844-2
  • Peer Reviewed
• [Journal Article] Oral ulceration: an unusual manifestation of lymphomatoid granulomatosis. (2019)
  • Author(s): Kidoguchi K, Yoshimura M, Kojima K*, Ureshino H, Egashira R, Yokoo M, Kai K, Egashira Y, Ohshima K, Ando T, Kimura S.
  • Journal Title: Ann Hematol Volume: 98 Issue: 5 Pages: 1305-1307
  • DOI: 10.1007/s00277-018-3506-3
  • Peer Reviewed
• [Journal Article] Clinical impact of the CONUT score and mogamulizumab in adult T cell leukemia/lymphoma. (2019)
  • Author(s): Ureshino H, Kusaba K, Kidoguchi K, Sano H, Nishioka A, Itamura H, Yoshimura M, Yokoo M, Shindo T, Kubota Y, Ando T, Kojima K, Sueoka E, Kimura S.
  • Journal Title: Annals of Hematology Volume: 98 Issue: 2 Pages: 465-471
  • DOI: 10.1007/s00277-018-3502-7
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. (2019)
  • Author(s): Ishizawa J, Zarabi SF, Davis RE, Halgas O, Nii T, Jitkova Y, Zhao R, St-Germain J, Heese LE, Egan G, Ruvolo VR, Barghout SH, Nishida Y, Hurren R, Ma W, Gronda M, Link T, Wong K, Mabanglo M, Kojima K, Andreeff M
  • Journal Title: Cancer Cell Volume: 35 Issue: 5 Pages: 721-737
  • DOI: 10.1016/j.ccell.2019.03.014
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia (2019)
  • Author(s): Nii T, Prabhu VV, Ruvolo V, Madhukar N, Zhao R, Mu H, Heese L, Nishida Y, Kojima K, Garnett MJ, McDermott U, Benes CH, Charter N, Deacon S, Elemento O, Allen JE, Oster W, Stogniew M, Ishizawa J, Andreeff M.
  • Journal Title: Leukemia Volume: 33 Issue: 12 Pages: 2805-2816
  • DOI: 10.1038/s41375-019-0491-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Locally distributed multicentric plasmacytomas in the ileum secondary to lymphoma chemoimmunotherapy (2019)
  • Author(s): Yokoo M, Kojima K, Sano H, Kai K, Arakawa F, Ohshima K, Matsunaga T, Kimura S.
  • Journal Title: Ann Hematol Volume: 98 Issue: 6 Pages: 1501-1503
  • DOI: 10.1007/s00277-018-3543-y
  • Peer Reviewed
• [Journal Article] Is clinicopathological distinction of mucosa-associated lymphoid tissue lymphoma from Waldenstrom macroglobulinemia essential in MYD88 L265P mutation-positive cases? (2019)
  • Author(s): Kidoguchi K, Kojima K, Seki R, Nagafuji K, Ohshima K, Kimura S.
  • Journal Title: Int J Hematol. Volume: 109 Issue: 3 Pages: 247-248
  • DOI: 10.1007/s12185-018-02585-8
  • Peer Reviewed
• [Journal Article] BCR-ABL1- and CBFB-MYH11-positive chronic myeloid leukemia presenting with primary blast crisis and marrow fibrosis. (2019)
  • Author(s): Kidoguchi K, Kojima K*, Yokoo M, Kimura S.
  • Journal Title: Ann Hematol. Volume: 98 Issue: 10 Pages: 2461-2462
  • DOI: 10.1007/s00277-019-03779-8
  • Peer Reviewed
• [Journal Article] Feasibility of the Imatinib Stop Study in the Japanese Clinical Setting: Delightedly Overcome CML Expert Stop TKI Trial (DOMEST Trial). (2018)
  • Author(s): Fujisawa S, Ueda Y, Usuki K, Kobayashi K, Kondo E, Doki N, Nakao T, Kanda Y, Kosugi N, Kosug H, Kumagai T, Harada H, Shikami M, Maeda Y, Sakura T, Inokuchi K, Saito A, Nawa Y, Ogasawara M, Nishida J, Kondo T, Yoshida C, Kuroda H, Tabe Y, Maeda Y, Imajo K, Kojima K, Morita S, Komukai S, Kawaguchi A, Sakamoto J, Kimura S
  • Journal Title: International Journal of Clinical Oncology Volume: 24 Issue: 4 Pages: 445-453
  • DOI: 10.1007/s10147-018-1368-2
  • Peer Reviewed
• [Journal Article] Targeting of BMI-1 expression by the novel small molecule PTC596 in mantle cell lymphoma. (2018)
  • Author(s): Maeda A, Nishida Y, Weetall M, Cao L, Branstrom A, Ishizawa J, Nii T, Schober WD, Abe Y, Matsue K, Yoshimura M, Kimura S, Kojima K.
  • Journal Title: Oncotarget. Volume: 19 Issue: 47 Pages: 28547-28560
  • DOI: 10.18632/oncotarget.25558
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition. (2018)
  • Author(s): Ishizawa J, Nakamaru K, Seki T, Tazaki K, Kojima K, Chachad D, Zhao R, Heese L, Ma W, Ma MCJ, DiNardo C, Pierce S, Patel KP, Tse A, Davis RE, Rao A, Andreeff M.
  • Journal Title: Cancer Res. Volume: 78 Issue: 10 Pages: 2721-2731
  • DOI: 10.1158/0008-5472.can-17-0949
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Successful treatment of post-transplant relapsed adult T cell leukemia after cord blood transplantation with low-dose, short-term lenalidomide (2018)
  • Author(s): Ando Toshihiko、Kojima Kensuke、Sano Haruhiko、Kidoguchi Keisuke、Kusaba Kana、Yoshimura Mariko、Yokoo Masako、Kubota Yasushi、Nakamura Hideaki、Takase Yukari、Aishima Shinichi、Kimura Shinya
  • Journal Title: Leukemia & Lymphoma Volume: in press Issue: 10 Pages: 1-4
  • DOI: 10.1080/10428194.2018.1427859
  • Peer Reviewed / Open Access
• [Journal Article] Predictive gene signatures determine tumor sensitivity to MDM2 inhibition. (2018)
  • Author(s): Ishizawa J, Nakamaru K, Seki T, Tazaki K, Kojima K, Chachad D, Zhao R, Heese LE, Ma W, Ma MCJ, DiNardo CD, Pierce SA, Patel KP, Tse A, Davis RE, Rao A, Andreeff M.
  • Journal Title: Cancer Res. Volume: in press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cells. (2017)
  • Author(s): Nishida Y, Maeda A, Kim MJ, Cao L, Kubota Y, Ishizawa J, AlRawi A, Kato Y, Iwama A, Fujisawa M, Matsue K, Weetall M, Dumble M, Andreeff M, Davis TW, Branstrom A, Kimura S, Kojima K.
  • Journal Title: Blood Cancer J Volume: 17 Issue: 2 Pages: e527-e527
  • DOI: 10.1038/bcj.2017.8
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Automatic digital quantification of bone marrow myeloma volume in appendicular skeletons - clinical implications and prognostic significance (2017)
  • Author(s): Nishida Yuki、Kimura Shinya、Mizobe Hideaki、Yamamichi Junta、Kojima Kensuke、Kawaguchi Atsushi、Fujisawa Manabu、Matsue Kosei
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 12885-12885
  • DOI: 10.1038/s41598-017-13255-w
  • Peer Reviewed / Open Access
• [Journal Article] Elderly patients with chronic myeloid leukemia benefit from a dasatinib dose as low as 20 mg. (2017)
  • Author(s): Itamura H, Kubota Y, Shindo T, Ando T, Kojima K, Kimura S
  • Journal Title: Clin Lymph Myeloma Leuk Volume: 印刷中 Issue: 6 Pages: 370-374
  • DOI: 10.1016/j.clml.2017.02.023
  • Peer Reviewed
• [Presentation] The novel imipridone ONC212 highly synergizes with the BCL-2 inhibitor ABT-199 in AML and activates orphan receptor GPR132. (2018)
  • Author(s): Nii T, Ishizawa J, Prabhu VV, Ruvolo V, Madhukar N, Zhao R, Mu H, Heese L, Kojima K, Garnett M, McDermott U, Benes C, Charter N, Deacon S, Elemento O, Allen J, Oster W, Stogniewand M, Andreeff M.
  • Organizer: 018 American Association for Cancer Research (AACR) Annual Meeting
  • Int'l Joint Research
• [Presentation] FLT3阻害 (2018)
  • Author(s): 小島研介
  • Organizer: 第22回日本がん分子標的治療学会学術集会
  • Invited
• [Presentation] Downregulation of BMI-1 By the Small Molecule PTC596 Induces Mitochondrial Apoptosis in Mantle Cell Lymphoma (2017)
  • Author(s): Kensuke Kojima, Aya Maeda, Sho Okamoto, Yuki Nishida, Cao Liangl, Marla Weetall, Art Branstrom and Shinya Kimura
  • Organizer: 59th Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Inhibition of Translation Initiation and Heat Shock Factor 1 (HSF1): A Novel Strategy Targeting FLT3 Double Mutant and Non-FLT3 Mutant AML Progenitor/Stem Cells (2017)
  • Author(s): Jo Ishizawa, Ran Zhao, Lauren Heese, Alex Jaeger, Yuki Nishida, Rodrigo Jacamo, Kensuke Kojima, Man Chun John MA, Vivian Ruvolo, Dhruv Chachad, R. Eric Davis, William Devine, John A Porco Jr., Luke Whitesell and Michael Andreeff
  • Organizer: 59th Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] PTC299 Is a Novel DHODH Inhibitor That Modulates VEGFA mRNA Translation and Inhibits Proliferation of a Broad Range of Leukemia Cells (2017)
  • Author(s): Liangxian Cao, Arthur Branstrom, John Baird, Christopher Trotta, Joseph Colacino, Marianne T. Santaguida, Diane Heiser, Mark Ma, Kensuke Kojima, Stuart Peltz, Edward O'Mara, Robert Spiegel and Marla Weetall
  • Organizer: 59th Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] The Novel Imipridone ONC212 Induces Pronounced Anti-Leukemia Effects in Vitro and In Vivo and Is Highly Synergistic with the BCL-2 Inhibitor ABT-199 (2017)
  • Author(s): Takenobu Nii, Jo Ishizawa, Varun Vijay Prabhu, Vivian Ruvolo, Neel Madhukar, Ran Zhao, Hong Mu, Lauren Heese, Kensuke Kojima, Mathew Garnett, Ultan McDermott, Cyril H Benes, Neil Charter, Sean Deacon, Olivier Elemento, Joshua E. Allen, Wolfgang Oster, Martin Stogniew and Michael Andreeff
  • Organizer: 59th Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Automatic Digital Quantification of Bone Marrow Myeloma Volume in Appendicular Skeletons ― Clinical Implications and Prognostic Significance (2017)
  • Author(s): Yuki Nishida, Shinya Kimura, Hideaki Mizobe, Junta Yamamichi, Kensuke Kojima, Atsushi Kawaguchi, Manabu Fujisawa and Kosei Matsue
  • Organizer: 59th Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Targeting of BMI-1 in mantle cell lymphoma (2017)
  • Author(s): Aya Maeda, Shinya Kimura, Kensuke Kojima
  • Organizer: 第76回日本癌学会学術総会
• [Remarks] 高知大学医学部血液内科学講座ウェブサイト
  • URL: http://www.kochi-u.ac.jp/kms/hemat/index.html
• [Remarks] 佐賀大学医学部附属病院 血液・呼吸器・腫瘍内科
  • URL: http://www.saga-hor.jp/main/