Circumventing resistance at bone marrow microenvironment in acute myeloid leukemia

• Project/Area Number: 25461412
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kobe University
• Principal Investigator: Minami Yosuke 神戸大学, 医学部附属病院, 講師 (60513752)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 白血病 / 分子標的療法 / ヘッジホッグシグナル / SMO阻害剤 / NANOG / ヘッジホッグ / 急性骨髄性白血病 / 白血病幹細胞 / 抗がん剤耐性 / がん微小環境

Outline of Final Research Achievements

Smoothened (SMO) regulates the Hedgehog (Hh) pathway. Gene set enrichment analysis (GSEA) revealed that SMO inhibitor treatment induced effects on the self-renewal signatures and the cell-cycling regulations associated with leukemic stem cells (LSCs)-like properties. I examined the pluripotency factor, NANOG expression in bone marrow cells, based on the previous report that downstream effectors in the Hh pathway, GLI directly binds to the NANOG promoter and that the GLI- NANOG axis promotes stemness and growth in several cancers. Change of NANOG transcripts was closely associated with the GLI-target genes. Furthermore, by backing to the pre-clinical experimental systems, NANOG transcript level decreased during SMO inhibitor treatment. GSEA revealed that treatment with SMO inhibitor modulates self-renewal and cell-cycling signatures in AML. NANOG transcript can be a responsive biomarker during the therapy.

Research Products

• [Journal Article] Perturbation of energy metabolism by fatty-acid derivative AIC-47 and imatinib in BCR-ABL harboring leukemic cells (2016)
  • Author(s): H Shinohara, M Kumazaki, Y Minami, N Sugito, Y Kuranaga, K Taniguchi, N Yamada, T Naoe, and Y Akao
  • Journal Title: Cancer Letter Volume: 371
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Wnt signaling is associated with cell survival in the interaction between acute myeloid leukemia cells and stromal cells (2016)
  • Author(s): Y Niwa, Y Minami, A Abe, F Hayakawa, K Yamada, and T Naoe
  • Journal Title: Leukemia and Lymphoma Volume: 未定
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Anti-cancer fatty-acid derivative induces autophagic cell death through modulation of PKM isoforms expression profile mediated by bcr-abl in chronic myeloid leukemia. (2015)
  • Author(s): Shinohara H, Taniguchi K, Kumazaki M, Yamada N, Ito Y, Otsuki Y, Uno B, Hayakawa F, Minami Y, Naoe T, Akao Y.
  • Journal Title: Cancer Letters Volume: 360 Issue: 1 Pages: 28-38
  • DOI: 10.1016/j.canlet.2015.01.039
  • Peer Reviewed / Open Access
• [Journal Article] Cancer stem cell and tumor environment (2015)
  • Author(s): Y Minami
  • Journal Title: Oncology Volume: 89 Issue: Suppl. 1 Pages: 22-24
  • DOI: 10.1159/000431060
• [Journal Article] Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained complete molecular response for at least 1 year: the prospective, multicentre Dasatinib-Discontinuation (DADI) Trial (2015)
  • Author(s): J Imagawa, H Tanaka, M Okada, H Nakamae, M Hino, K Murai, Y Ishida, T Kumagai, S Sato, K Ohashi, H Sakamaki, H Wakita, N Uoshima, Y Nakagawa, Y Minami, M Ogasawara, T Takeoka, H Akasaka, T Utsumi, N Uike, T Sato, H Sakai, K Usuki, S Morita, J Sakamoto, and S Kimura, on behalf of the DADI Trial Group, JAPAN
  • Journal Title: Lancet Haematology Volume: 2 Issue: 12 Pages: e528-e535
  • DOI: 10.1016/s2352-3026(15)00196-9
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Properties of chronic myeloid leukemia stem cells: strategy based on the kinetics during treatment with ABL-tyrosine kinase inhibitors (2014)
  • Author(s): Y Minami
  • Journal Title: J Hematol Transfus Volume: 2 Pages: 1025-1029
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Heme-related molecules induce rapid production of neutrophil extracellular traps (2014)
  • Author(s): M Kono, K Saigo, Y Takagi, T Takahashi, S Kawauchi, A Wada, M Hashimoto, Y Minami, S Imoto, M Takenokuchi, T Morikawa, and K Funakoshi
  • Journal Title: Transfusion Volume: 54 Issue: 11 Pages: 2811-2819
  • DOI: 10.1111/trf.12700
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phosphorylated Sp1 is the regulator of DNA-PKcs and DNA ligase IV transcription of daunorubicin-resistant leukemia cell lines. (2014)
  • Author(s): Nishida Y, Mizutani N, Inoue M, Omori Y, Tamiya-Koizumi K, Takagi A, Kojima T, Suzuki M, Nozawa Y, Minami Y, Ohnishi K, Naoe T, Murate T.
  • Journal Title: Biochim Biophys Acta. Volume: 1839 Issue: 4 Pages: 265-274
  • DOI: 10.1016/j.bbagrm.2014.02.004
  • Peer Reviewed
• [Journal Article] Combination of Ponatinib with Hedgehog Antagonist Vismodegib for Therapy-Resistant BCR-ABL1-Positive Leukemia. (2013)
  • Author(s): Katagiri S, Minami Y, Naoe T, et al.
  • Journal Title: Clin Cancer Res. Volume: 19 Issue: 6 Pages: 1422-1432
  • DOI: 10.1158/1078-0432.ccr-12-1777
  • Peer Reviewed
• [Journal Article] Functionally Deregulated AML1/RUNX1 Cooperates with BCR-ABL to Induce a Blastic Phase-Like Phenotype of Chronic Myelogenous Leukemia in Mice. (2013)
  • Author(s): Kiyoko Yamamoto, Shinobu Tsuzuki, Yosuke Minami, Yukiya Yamamoto, Akihiro Abe, Koichi Ohshima, Masao Seto, Tomoki Naoe.
  • Journal Title: PLOS ONE Volume: 8 Issue: 9 Pages: e74864-e74864
  • DOI: 10.1371/journal.pone.0074864
  • Peer Reviewed
• [Journal Article] Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia (2013)
  • Author(s): Takashi Shibata, Yosuke Minami, Ayako Mitsuma, Sachi Morita, Megumi Inoue, Tomoya Shimokata, Mihoko Sugishita, Tomoyo Oguri, Tomoki Naoe, Yuichi Ando
  • Journal Title: International Journal of Clinical Oncology Volume: (in press) Issue: 2 Pages: 391-396
  • DOI: 10.1007/s10147-013-0562-5
  • Peer Reviewed
• [Presentation] Biomarker and gene profiling analyses in acute myeloid leukemia during treatment with Hedgehog signaling inhibitor (2015)
  • Author(s): Seiji Kakiuchi, Yosuke Minami, Nobuaki Fukushima, Hiroshi Matsuoka, Tomoki Naoe, Hironobu Minami
  • Organizer: 米国血液学会
  • Place of Presentation: オーランド
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] 急性骨髄性白血病に対するヘッジホッグ阻害剤PF-913による効果とバイオマーカーの検討 (2014)
  • Author(s): 南陽介
  • Organizer: 第７６回日本血液学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31
• [Presentation] ヘッジホッグ阻害剤PF-913によるAML幹細胞に対する効果とバイオマーカー (2014)
  • Author(s): 南陽介
  • Organizer: 第１２回臨床腫瘍学会総会
  • Place of Presentation: 福岡
  • Year and Date: 2014-07-17
• [Presentation] Treatment with Hedgehog inhibitor, PF-913, attenuates leukemia-initiation potential in acute myeloid leukemia cells (2014)
  • Author(s): Y Minami, N Fukushima, H Minami, A Sadarangani, C Jamieson, and T Naoe
  • Organizer: Keystone Symposia, Stem Cells and Cancer
  • Place of Presentation: Banff, Canada
• [Presentation] Treatment with Hedgehog inhibitor, PF-913, attenuates leukemia-initiation potential in acute myeloid leukemia cells (2014)
  • Author(s): Y Minami, N Fukushima, H Minami, A Sadarangani, C Jamieson, and T Naoe
  • Organizer: AACR Annual Meeting 2014
  • Place of Presentation: San Diego, USA
• [Book] がん分子標的治療 (2014)
  • Author(s): 南陽介
  • Total Pages: 4
  • Publisher: メディカルビュー社
• [Book] がん分子標的治療 (2014)
  • Author(s): 直江知樹 南陽介
  • Total Pages: 5
  • Publisher: メディカルビュー社
• [Book] 血液フロンティア (2014)
  • Author(s): 南陽介 直江知樹
  • Total Pages: 6
  • Publisher: 医薬ジャーナル社