Functional disruption of leukemia microenvironment by leukemia p53

• Project/Area Number: 26461425
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Saga University
• Principal Investigator: KOJIMA KENSUKE 佐賀大学, 医学部, 准教授 (10332793)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 白血病 / p53 / 微小環境 / 幹細胞 / MDM2 / 造血微小環境

Outline of Final Research Achievements

We investigated an interaction between leukemia cells and stromal cells. Using newly developed leukemia microenvironment models, we found that (1) p53 activation by irradiation, treatment with certain classes of chemotherapeutic agents or MDM2 inhibition can decrease expression levels of PD-L1 in leukemia cells and reduce secretion of SDF-1 (CXCL12) from stromal cells, and (2) BMI-1 inhibition actively disrupt the leukemia-stroma interaction through inducing cell death in leukemia cells and inhibiting stromal functions. Novel strategies targeting leukemia-stroma interaction may improve therapeutic outcome of leukemias.

Research Products

• [Int'l Joint Research] MD ANderson Cancer Center(米国)
• [Int'l Joint Research] MD Anderson Cancer Center(米国)
• [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] FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B cell acute leukemia. (2017)
  • Author(s): Ishizawa J, Sugihara E, Kuninaka S, Mogushi K, Kojima K, Benton CB, Zhao R, Chachad D, Hashimoto N, Jacamo RO, Qiu Y, Yoo SY, Okamoto S, Andreeff M, Kornblau SM, Saya H.
  • Journal Title: Blood Volume: 129 Issue: 14 Pages: 1958-1968
  • DOI: 10.1182/blood-2016-07-726216
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The pathophysiological significance of PPM1D and therapeutic targeting of PPM1D-mediated signaling by GSK2830371 in mantle cell lymphoma. (2016)
  • Author(s): Kojima K, Maeda A, Yoshimura M, Nishida Y, Kimura S.
  • Journal Title: Oncotarget Volume: 7 Issue: 43 Pages: 69625-69637
  • DOI: 10.18632/oncotarget.11904
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pharmacological activation of wild-type p53 in the therapy of leukemia. (2016)
  • Author(s): Kojima K, Ishizawa J, Andreeff M.
  • Journal Title: Exp Hematol Volume: 44 Issue: 9 Pages: 791-798
  • DOI: 10.1016/j.exphem.2016.05.014
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. (2016)
  • Author(s): Ishizawa J, Kojima K, Chachad D, Ruvolo P, Ruvolo V, Jacamo RO, Borthakur G, Mu H, Zeng Z, Tabe Y, Allen JE, Wang Z, Ma W, Lee HC, Orlowski R, Sarbassov dos D, Lorenzi PL, Huang X, Neelapu SS, McDonnell T, Miranda RN, Wang M, Kantarjian H, Konopleva M, Davis RE, Andreeff M.
  • Journal Title: Sci Signal. Volume: 9 Issue: 415
  • DOI: 10.1126/scisignal.aac4380
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia. (2016)
  • Author(s): Andreeff M, Kelly KR, Yee K, Assouline S, Strair R, Popplewell L, Bowen D, Martinelli G, Drummond MW, Vyas P, Kirschbaum M, Iyer SP, Ruvolo V, González GM, Huang X, Chen G, Graves B, Blotner S, Bridge P, Jukofsky L, Middleton S, Reckner M, Rueger R, Zhi J, Nichols G, Kojima K.
  • Journal Title: Clinical Cancer Research Volume: 22 Issue: 4 Pages: 868-876
  • DOI: 10.1158/1078-0432.ccr-15-0481
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Preclinical activity of the novel BMI-1 inhibitor PTC-209 in acute myeloid leukemia: implications for leukemia therapy. (2015)
  • Author(s): Nishida Y, Maeda A, Chachad D, Ishizawa J, Yi Hua Q, Kornblau SM, Kimura S, Andreeff M, Kojima K.
  • Journal Title: Cancer Science Volume: 106 Issue: 12 Pages: 1705-1713
  • DOI: 10.1111/cas.12833
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mitochondrial profiling of acute myeloid leukemia in the assessment of response to apoptosis modulating drugs. (2015)
  • Author(s): Ishizawa J, Kojima K, McQueen T, Ruvolo V, Chachad D, Nogueras-Gonzalez GM, Huang X, Pierceall WE, Dettman EJ, Cardone MH, Shacham S, Konopleva M, Andreeff M.
  • Journal Title: PLoS One Volume: 10 Issue: 9 Pages: 2715-27
  • DOI: 10.1371/journal.pone.0138377
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Expression, function, and targeting of the nuclear exporter chromosome region maintenance 1 (CRM1) protein. (2015)
  • Author(s): Ishizawa J, Kojima K, Hail N Jr, Tabe Y, Andreeff M.
  • Journal Title: Pharmacol Ther. Volume: 153 Pages: 25-35
  • DOI: 10.1016/j.pharmthera.2015.06.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ribosomal biogenesis and translational flux inhibition by the selective inhibitor of nuclear export (SINE) XPO1 antagonist KPT-185. (2015)
  • Author(s): Yoko Tabe, Kensuke Kojima, Shinichi Yamamoto, Kazumasa Sekihara, Hiromichi Matsushita, Richard Eric Davis, Zhiqiang Wang, Wencai Ma, Jo Ishizawa, Saiko Kazuno, Michael Kauffman, Sharon Shacham, Tsutomu Fujimura, Takashi Ueno, Takashi Miida, Michael Andreef
  • Journal Title: PLoS One Volume: 10 Issue: 9 Pages: e0137210-e0137210
  • DOI: 10.1371/journal.pone.0137210
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression. (2015)
  • Author(s): Harada M, Benito J, Yamamoto S, Kaur S, Arslan D, Ramirez S, Jacamo R, Platanias L, Matsushita H, Fujimura T, Kazuno S, Kojima K, Tabe Y, Konopleva M.
  • Journal Title: Oncotarget Volume: 6 Issue: 35 Pages: 37930-37947
  • DOI: 10.18632/oncotarget.6122
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] MDM2 Inhibitor, Nutlin 3a, induces p53 dependent autophagy in acute leukemia by AMP kinase activation. (2015)
  • Author(s): Borthakur G, Duvvuri S, Ruvolo V, Tripathi DN, Piya S, Burks J, Jacamo R, Kojima K, Ruvolo P, Fueyo-Margareto J, Konopleva M, Andreeff M. MDM2 Inhibitor, Nutlin 3a, induces p53 dependent autophagy in acute leukemia by AMP kinase activation.
  • Journal Title: PLoS One Volume: 10 Issue: 10 Pages: e0139254-e0139254
  • DOI: 10.1371/journal.pone.0139254
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] "Coexistence of ALK- anaplastic large cell lymphoma and CD4+ T-cell large granular lymphocytic leukemia " (2015)
  • Author(s): Kazuharu Kamachi1, Noriyasu Fukushima, Toshihiko Ando, Ken-ichi Sato, Koichi Ohshima, Masako Yokoo, Takero Shindo, Yasushi Kubota, Kensuke Kojima, Shinya Kimura
  • Journal Title: Ann Hematol Volume: 94 Issue: 3 Pages: 539-540
  • DOI: 10.1007/s00277-014-2176-z
  • Peer Reviewed
• [Journal Article] Reactivation of resolved infection with the hepatitis B virus immune escape mutant G145R during dasatinib treatment for chronic myeloid leukemia. (2015)
  • Author(s): Ando T, Kojima K, Isoda H, Eguchi Y, Honda T, Ishigami M, Kimura S.
  • Journal Title: Int J Hematol. Volume: 101 Pages: 1-1
• [Journal Article] Induction of p53-mediated transcription and apoptosis by Exportin-1 (XPO1) inhibition in mantle cell lymphoma. (2014)
  • Author(s): 4.Yoshimura M, Ishizawa J, Ruvolo V, Dilip A, Quintas-Cardama A, McDonnell TJ, Neelapu SS, Kwak LW, Shacham S, Kauffman M, Tabe Y, Yokoo M, Kimura S, Andreeff M, Kojima K
  • Journal Title: Cancer Sci. Volume: 105 Issue: 7 Pages: 795-801
  • DOI: 10.1111/cas.12430
  • Peer Reviewed
• [Journal Article] Diffuse bone marrow uptake of fluorodeoxyglucose in a patient with aleukaemic acute lymphoblastic leukaemia. (2014)
  • Author(s): Kitamura H, Ando T, Kojima K, Komiya K, Sueoka-Aragane N, Kimura S.
  • Journal Title: Br J Haematol. Volume: 166 Issue: 1 Pages: 2-2
  • DOI: 10.1111/bjh.12872
  • Peer Reviewed
• [Journal Article] Small lymphocytic lymphoma presenting as bulky renal incidentaloma. (2014)
  • Author(s): Kamachi K, Kojima K, Nishijima A, Takeshita M, Ando T, Kimura S.
  • Journal Title: Int J Hematol. Volume: 100 Issue: 2 Pages: 107-108
  • DOI: 10.1007/s12185-014-1609-8
  • Peer Reviewed
• [Journal Article] ABL tyrosine kinase inhibitor–induced pulmonary alveolar proteinosis in chronic myeloid leukemia (2014)
  • Author(s): Mariko Yoshimura, Kensuke Kojima, Rika Tomimasu, Noriyasu Fukushima, Shinichiro Hayashi, Eisaburo Sueoka, Shinya Kimura
  • Journal Title: Int J Hematol Volume: 100 Issue: 6 Pages: 611-614
  • DOI: 10.1007/s12185-014-1666-z
  • Peer Reviewed
• [Presentation] The PPM1D inhibitor GSK2830371 has p53-dependent anti-lymphoma effects and enhances bortezomib-induced apoptosis in mantle cell lymphoma (2016)
  • Author(s): Kensuke Kojima, Mariko Yoshimura, Aya Maeda, Hiroaki Kitamura, Yuki Nishida, Shinya Kimura
  • Organizer: American Association for Cancer Research (AACR) 2016 Annual Meeting
  • Place of Presentation: New Orleans
  • Year and Date: 2016-04-19
  • Int'l Joint Research
• [Presentation] Targeting BMI-1 by the novel BMI-1 inhibitor PTC596 in acute leukemia (2015)
  • Author(s): Yuki Nishida, Aya Maeda, Liangxian Cao, Melissa Dumble, Shinya Kimura Thomas W. Davis and Kensuke Kojima
  • Organizer: 2015 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference
  • Place of Presentation: Boston
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] Preclinical activity of the novel BMI-1 inhibitor PTC-209 in acute myeloid leukemia (2015)
  • Author(s): Yuki Nishida, Aya Maeda, Shinya Kimura, Thomas W. Davis, Kensuke Kojima
  • Organizer: 日本血液学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-17
• [Presentation] マントル細胞リンパ腫におけるPPM1D阻害剤によるp53依存性のアポトーシス誘導効果 (2015)
  • Author(s): 吉村麻里子、木村晋也、小島研介
  • Organizer: 日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-10
• [Presentation] BMI-1 inhibition by PTC-209 induces mitochondrial apoptosis in acute myeloid leukemia cells (2015)
  • Author(s): Kensuke Kojima, Yuki Nishida, Aya Maeda, Dhruv Chachad, Hiroaki Kitamura, Jo Ishizawa, Michael Andreeff, Shinya Kimura
  • Organizer: American Association for Cancer Research (AACR) 2015 Annual Meeting
  • Place of Presentation: Philadelphia
  • Year and Date: 2015-04-21
  • Int'l Joint Research
• [Presentation] Prognostic impact and targeting of BMI-1 in acute myeloid leukemia (2014)
  • Author(s): Yuki Nishida, Kensuke Kojima, Aya Maeda, Dhruv Chachad, Hiroaki Kitamura, Jo Ishizawa, Michael Andreeff, Steven Kornblau, Shinya Kimura
  • Organizer: 56th ASH Annual Meeting and Exposition
  • Place of Presentation: San Francisco
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] p53と白血病 (2014)
  • Author(s): 小島研介
  • Organizer: 第76回日本血液学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
  • Invited
• [Presentation] マントル細胞リンパ腫における、XPO1阻害によるp53依存性転写の誘導と細胞死 (2014)
  • Author(s): 小島研介
  • Organizer: 第18回日本がん分子標的治療学会
  • Place of Presentation: 仙台
  • Year and Date: 2014-06-25 – 2014-06-27
• [Presentation] Induction of p53-mediated transcription and apoptosis by XPO1 inhibition in mantle cell lymphoma (2014)
  • Author(s): Kensuke Kojima
  • Organizer: 16th International p53 Workshop
  • Place of Presentation: Stockholm
  • Year and Date: 2014-06-15 – 2014-06-19
• [Book] Targeted Therapy of Acute Myeloid Leukemia. (2015)
  • Author(s): Kojima K, Vassilev LT.
  • Total Pages: 16
  • Publisher: Springer
• [Book] Targeted Therapy in Translational Cancer Research. (2015)
  • Author(s): Kojima K, Andreeff M.
  • Total Pages: 7
  • Publisher: John Wiley & Sons
• [Remarks] 佐賀大学医学部 血液・呼吸器・腫瘍内科
  • URL: http://www.saga-hor.jp/main/
• [Remarks] 佐賀大学医学部 血液・呼吸器・腫瘍内科＞スタッフ紹介
  • URL: http://www.saga-hor.jp/main/65.html