Molecular and cellular effects of tumor microenvironment-specific Galectin-3 in leukemia

• Project/Area Number: 23591403
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: KURODA Junya 京都府立医科大学, 医学(系)研究科(研究院), 講師 (70433258)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: ガレクチン-3 / 慢性骨髄性白血病 / 骨髄腫瘍環境 / 分子標的 / FTY720 / アポトーシス / BIM / BID / MCL-1 / ガレクチンー3 / 腫瘍環境 / 治療抵抗性

Research Abstract

We in this study investigated the molecular and biologic effects of galectin-3 (Gal-3) which is specifically induced by tumor-microenvironment in leukemic cells of chronic myelogenous leukemia (CML). Gal-3 promoted cell proliferation of leukemic cells via the activation of ERK and AKT as well as the inhibition of extracellular SERPINA1-albumin complex. Gal-3 also induced the expression of anti-apoptotic MCL-1 and caused the resistance to molecular targeted agents and genotoxic agents in CML cells. Interestingly, Gal-3 expression promoted the lodgment of leukemic cells in bone marrow in vivo. Finally, our study revealed that the combinatory use of protein phosphatase-2 activator in addition to the currently utilized molecular targeted agents, such as imatinib or dasatinib, was effective in overcoming those series of leukemia-promoting effects of Gal-3,

Research Products

• [Journal Article] Suppression of SERPINA1-albumin complex formation by galectin-3 overexpression leads to paracrine growth promotion of chronic myelogenous leukemic cells (2014)
  • Author(s): Nakayama R, Kuroda J, Taniyama N, Yamamoto-Sugitani M, Wada S, Kiyota M, Mizutani S, Chinen Y, Matsumoto Y, Nagoshi H, Shimura Y, Kobayashi T, Horiike S, Taniwaki M
  • Journal Title: Leukemia Res Volume: 38 Pages: 103-108
• [Journal Article] Suppression of SERPINA1-albumin complex formation by galectin-3 overexpression leads to paracrine growth promotion of chronic myelogenous leukemia cells. (2014)
  • Author(s): Nakayama R, Kuroda J, Taniyama N, Yamamoto-Sugitani M, Wada S, Kiyota M, Mizutani S, Chinen Y, Matsumoto Y, Nagoshi H, Shimura Y, Kobayashi T, Horiike S, Sato K, Taniwaki M.
  • Journal Title: Leukemia Research Volume: 38 Issue: 1 Pages: 103-108
  • DOI: 10.1016/j.leukres.2013.07.026
  • Peer Reviewed / Open Access
• [Journal Article] Multifaceted Mechanisms for Cell Survival in Chronic Myelogenous Leukemia (2013)
  • Author(s): Kuroda J, Yamamoto M, Sasaki N, Taniwaki M
  • Journal Title: Curr Cancer Drug Targets Volume: 13 Pages: 69-79
• [Journal Article] FTY720 induces apoptosis of chronic myelogenous leukemia cells via dual activation of BIM and BID and overcomes various types of resistance to tyrosine kinase inhibitors (2013)
  • Author(s): Kiyota M, Kuroda J, Yamamoto-Sugitani M, Shimura Y, Nakayama R, Nagoshi H, Mizutani S, Chinen Y, Sasaki N, Sakamoto N, Kobayashi T, Matsumoto Y, Horiike S, Taniwaki M
  • Journal Title: Apoptosis Volume: 18 Pages: 1437-46
• [Journal Article] FTY720 induces apoptosis of chronic myelogenous leukemia cells via dual activation of BIM and BID and overcomes various types of resistance to tyrosine kinase inhibitors. (2013)
  • Author(s): Kiyota M, Kuroda J, Yamamoto-Sugitani M, Shimura Y, Nakayama R, Nagoshi H, Mizutani S, Chinen Y, Sasaki N, Sakamoto N, Kobayashi T, Matsumoto Y, Horiike S, Taniwaki M.
  • Journal Title: Apoptosis Volume: 18 Issue: 11 Pages: 366-374
  • DOI: 10.1007/s10495-013-0882-y
  • Peer Reviewed
• [Journal Article] Editorial. The Innovative Decade of Molecular Targeted Therapy. (2013)
  • Author(s): Kuroda J
  • Journal Title: Translational Medicine Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Multifaceted Mechanisms for Cell Survival in Chronic Myelogenous Leukemia. (2013)
  • Author(s): Kuroda J, Yamamoto M, Sasaki N, Taniwaki M.
  • Journal Title: Curr Cancer Drug Targets Volume: 13 Pages: 69-79
  • Peer Reviewed
• [Journal Article] Editorial. The Innovative Decade of Molecular Targeted Therapy (2012)
  • Author(s): Kuroda J
  • Journal Title: Transl Med 2012
• [Journal Article] 慢性骨髄性白血病の薬剤耐性機構 (2012)
  • Author(s): 黒田純也
  • Journal Title: Annual Review血液2013 Volume: １ Pages: 99-108
• [Journal Article] Principles and current topics concerning management of tyrosine kinase inhibitor therapy for chronic myelogenous leukemia (2011)
  • Author(s): Kuroda J, Taniwaki M
  • Journal Title: Transl Med
• [Journal Article] Galectin-3 induced by leukemia microenvironment promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemia (2011)
  • Author(s): Yamamoto-Sugitani M, Kuroda J, Ashihara E, Nagoshi H, Kobayashi T, Matsumoto Y, Sasaki N, Shimura Y, Kiyota M, Nakayama R, Akaji K, Taki T, Uoshima N, Kobayashi Y, Horiike S, Maekawa T, Taniwaki M
  • Journal Title: Proc Natl Acad Sci USA Volume: 108 Pages: 17468-17473
• [Journal Article] 慢性骨髄性白血病の細胞死の抑制 (2011)
  • Author(s): 黒田純也、山本未央、谷脇雅史
  • Journal Title: 血液内科 Volume: 62(2) Pages: 159-165
• [Journal Article] Galectin-3 induced by leukemia microenvironment promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemia. (2011)
  • Author(s): Yamamoto-Sugitani M, Kuroda J, Ashihara E, Nagoshi H, Kobayashi T, Matsumoto Y, et al.
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 108 Pages: 17468-17473
  • Peer Reviewed
• [Presentation] 慢性骨髄性白血病に対するチロシンキナーゼ阻害剤治療 (2012)
  • Author(s): 黒田純也
  • Organizer: 第98回近畿血液学地方会
  • Year and Date: 2012-12-01
• [Presentation] Galectin-3 protects CML leukemic cells by antagonizing SERPINA1-albumin complex (2012)
  • Author(s): Nakayama R, Kuroda J, Taniyama N, Wada S, Sugitani M, Shimura Y, Nagoshi H, Mizutani S, Chinen Y, Sakamoto N, Kobayashi T, Matsumoto Y, Horiike S, Sato K, Taniwaki M
  • Organizer: 第74回日本血液学会学術集会
• [Presentation] FTY720 induces apoptosis via both Bim-mediated intrinsic and extrinsic pathway in CML (2012)
  • Author(s): Kiyota M, Kuroda J, Yamamoto-Sugitani M, Shimura Y, Nakayama R, Nagoshi H, Mizutani S, Chinen Y, Sakamoto N, Kobayashi T, Matsumoto Y, Horiike S, Taniwaki M
  • Organizer: 第74回日本血液学会学術集会
• [Presentation] Leukemia microenvironment-specific galectin-3 expression promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemia (2012)
  • Author(s): Yamamoto-Sugitani M, Kuroda J, Ashihara E, Nagoshi H, Kobayashi T, Matsumoto Y, Sasaki N, Shimura Y, Kiyota M, Nakayama R, Akaji K, Taki T, Uoshima N, Kobayashi Y, Horiike S, Maekawa T, Taniwaki M
  • Organizer: The 3^<rd> JSH International Symposium 2012
• [Presentation] Fingolimod (FTY720) Overcomes the Resistance to Tyrosine Kinase Inhibitors Via Dual Activation of BIM and BID in Chronic Myelogenous Leukemia The American Society of Hematology (2012)
  • Author(s): Kiyota M, Kuroda J, Yamamoto-Sugitani M, Shimura Y, Nakayama R, Nagoshi H, Mizutani S, Chinen Y, Sakamoto N, Kobayashi T, Matsumoto Y, Horiike S, Taki T, Taniwaki M
  • Organizer: 54th Annual Meeting and Exposition
• [Presentation] 慢性骨髄性白血病に対するチロシンキナーゼ阻害剤治療 (2012)
  • Author(s): 黒田純也.
  • Organizer: 第98回近畿血液学地方会
  • Place of Presentation: 京都
  • Invited
• [Presentation] Galectin-3 protects CML leukemic cells by antagonizing SERPINA1-albumin complex. (2012)
  • Author(s): Nakayama R, Kuroda J, Taniyama N, Wada S, Sugitani M, Shimura Y, Nagoshi H, Mizutani S, Chinen Y, Sakamoto N, Kobayashi T, Matsumoto Y, Horiike S, Sato K, Taniwaki M.
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] FTY720 induces apoptosis via both Bim-mediated intrinsic and extrinsic pathway in CML. (2012)
  • Author(s): Kiyota M, Kuroda J, Yamamoto-Sugitani M, Shimura Y, Nakayama R, Nagoshi H, Mizutani S, Chinen Y, Sakamoto N, Kobayashi T, Matsumoto Y, Horiike S, Taniwaki M.
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Fingolimod (FTY720) Overcomes the Resistance to Tyrosine Kinase Inhibitors Via Dual Activation of BIM and BID in Chronic Myelogenous Leukemia (2012)
  • Author(s): Kiyota M, Kuroda J, Yamamoto-Sugitani M, Shimura Y, Nakayama R, Nagoshi H, Mizutani S, Chinen Y, Sakamoto N, Kobayashi T, Matsumoto Y, Horiike S, Taki T, Taniwaki M.
  • Organizer: The American Society of Hematology 54th Annual Meeting and Exposition
  • Place of Presentation: Atlanta, USA
• [Presentation] Leukemia Microenvironment-Specific Galectin-3 Expression of Leukemic Cells Promotes Malignant Niche Formation and Bone Marrow Lodgment of Leukemic Cells in Chronic Myelogenous Leukemia (2011)
  • Author(s): Kuroda J, Yamamoto M, Ashihara E, Nagoshi H, Kobayashi T, Matsumoto Y, Sasaki N, Shimura Y, Kiyota M, Nakayama R, Horiike S, Maekawa T, Taniwaki M
  • Organizer: The American Society of Hematology 53rd Annual Meeting and Exposition
  • Year and Date: 2011-12-11
• [Presentation] Galectin-3 Is the Molecular Target for Overcoming Multidrug Resistance Due to the Cell Protection by Bone Marrow Leukemia Microenvironment in Chronic Myeloid Leukemia (2011)
  • Author(s): Yamamoto M, Kuroda J, Kobayashi T, Sasaki N, Nagoshi H, Shimura Y, Kiyota M, Nakayama R, Horiike S, Ashihara E, Akaji K, Taniwaki M
  • Organizer: The American Society of Hematology 53rd Annual Meeting and Exposition
  • Year and Date: 2011-12-11
• [Presentation] Leukemia Microenvironment-Specific Galectin-3 Expression of Leukemic Cells Promotes Malignant Niche Formation and Bone Marrow Lodgment of Leukemic Cells in Chronic Myelogenous Leukemia. (2011)
  • Author(s): Kuroda J, Yamamoto M, Ashihara E, Nagoshi H, Kobayashi T, Matsumoto Y, Sasaki N, Shimura Y, Kiyota M, Nakayama R, Horiike S, Maekawa T, Taniwaki M.
  • Organizer: The American Society of Hematology 53rd Annual Meeting and Exposition
  • Place of Presentation: USA
• [Book] 慢性骨髄性白血病の薬剤耐性機構. Annual Review血液2013 (2013)
  • Author(s): 黒田純也
  • Publisher: 中外医学社
• [Book] 慢性骨髄性白血病に対するチロシンキナーゼ阻害剤治療-知っておきたい基礎知識- BLOOD MASTER Vol.8「慢性骨髄性白血病」 (2011)
  • Author(s): 黒田純也, (前川平編)
  • Publisher: 大日本住友製薬