Identification of a critical epigenetic mechanism via histone modification in drug resistance of blood cancer cells.

• Project/Area Number: 23591405
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Jichi Medical University
• Principal Investigator: KIKUCHI Jiro 自治医科大学, 医学部, 准教授 (60371035)
• Co-Investigator(Renkei-kenkyūsha): FURUKAWA Yusuke 自治医科大学, 医学部, 教授 (00199431)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 血液腫瘍学 / エピジェネティクス / 薬剤耐性 / 造血器腫瘍 / ヒストン修飾 / 国際情報交流

Research Abstract

Cell adhesion mediated-drug resistance (CAM-DR) is a major obstacle in achieving cure in patients with hematologic malignancies including multiple myeloma (MM). We found that di or trimethylation was moderately induced in histone H3 lysine 4 (K4) and K36, and markedly in K9 and K27 by anti-MM drug treatment without adhesion to stromal cells. In contrast, trimethylation to K27 (H3K27me3) was absent in cell adhesion mediated-drug resistant MM cells. Inhibition of H3K27me3 significantly inhibited anti-MM drug-induced apoptosis in stroma free condition. These results suggest that cell adhesion-induced H3K27me3 inhibition is a critical step in drug resistance of MM cells.

Research Products

• [Journal Article] Suitable drug combination with bortezomib for multiple myeloma under stroma-free conditions and in contact with fibronectin or bone marrow stromal cells. (2014)
  • Author(s): Kikuchi J, Koyama D, Mukai YH, and Furukawa Y.
  • Journal Title: Int J Hematol Volume: in press Issue: 6 Pages: 726-736
  • DOI: 10.1007/s12185-014-1573-3
  • Peer Reviewed
• [Journal Article] Proteasome inhibitors exert cytotoxicity and increase chemosensitivity via transcriptional repression of Notch1 in T-cell acute lymphoblastic leukemia. (2014)
  • Author(s): Koyama D, Kikuchi J, Hiraoka N, Wada T, Kurosawa H, Chiba S, and Furukawa Y.
  • Journal Title: Leukemia Volume: in press Issue: 6 Pages: 1216-1226
  • DOI: 10.1038/leu.2013.366
  • Peer Reviewed / Open Access
• [Journal Article] Romidepsin overcomes cell adhesion- mediated drug resistance in multiple myeloma cells (2013)
  • Author(s): Sripayap P, Nagai T, Noborio-Hatano K, Kikuchi J, Furukawa Y, and Ozawa K
  • Journal Title: Acta Hematol Volume: 132 Pages: 1-4
• [Journal Article] Alkylating agents induce histone H3K18 hyperacetylation and potentiate HDAC inhibitor-mediated global histone acetylation and cytotoxicity in mantle cell lymphoma (2013)
  • Author(s): Hiraoka N, Kikuchi J, Koyama D, Wada T, Mori S, Nakamura Y, and Furukawa Y
  • Journal Title: Blood Cancer J Volume: 3
• [Journal Article] The novel orally active proteasome inhibitor K-7174 exerts anti-myeloma activity in vitro and in vivo by down-regulating the expression of class I histone deacetylases (2013)
  • Author(s): Kikuchi J, Yamada S, Koyama D, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, and Furukawa Y
  • Journal Title: J Biol Chem Volume: 288 Pages: 25593-25602
• [Journal Article] Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding (2013)
  • Author(s): Kikuchi J, Shibayama N, Yamada S, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, Sugiyama K, Ohki M, Park SY, and Furukawa Y
  • Journal Title: PLoS One Volume: 8
• [Journal Article] HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias (2013)
  • Author(s): Calero-Nieto FJ, Joshi A, Bonadies N, Kinston S, Chan WI, Gudgin E, Pridans C, Landry JR, Kikuchi J, Huntly BJ, and Gottgens B
  • Journal Title: Oncogene Volume: 32
• [Journal Article] BCR-ABL regulates death receptor expression for TNF-related apoptosis-inducing ligand (TRAIL) in Philadelphia chromosome- positive leukemia (2013)
  • Author(s): Kuroda I, Inukai T, Zhang X, Kikuchi J, Furukawa Y, Nemoto A, Akahane K, Hirose K, Honna-Oshiro H, Goi K, Kagami K, Yagita H, Tauchi T, Maeda Y, Sugita K
  • Journal Title: Oncogene Volume: 32 Pages: 1670-1681
• [Journal Article] Romidepsin overcomes cell adhesion-mediated drug resistance in multiple myeloma cells. (2013)
  • Author(s): Sripayap P, Nagai T, Noborio-Hatano K, Kikuchi J, Furukawa Y, and Ozawa K.
  • Journal Title: Acta Hematol Volume: 132 Pages: 1-4
  • Peer Reviewed
• [Journal Article] Alkylating agents induce histone H3K18 hyperacetylation and potentiate HDAC inhibitor-mediated global histone acetylation and cytotoxicity in mantle cell lymphoma. (2013)
  • Author(s): Hiraoka N, Kikuchi J, Koyama D, Wada T, Mori S, Nakamura Y, and Furukawa Y.
  • Journal Title: Blood Cancer J Volume: 3 Issue: 12 Pages: 2169-2169
  • DOI: 10.1038/bcj.2013.66
  • Peer Reviewed
• [Journal Article] The novel orally active proteasome inhibitor K-7174 exerts anti-myeloma activity in vitro and in vivo by down-regulating the expression of class I histone deacetylases. (2013)
  • Author(s): Kikuchi J, Yamada S, Koyama D, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, and Furukawa Y.
  • Journal Title: J Biol Chem Volume: 288 Issue: 35 Pages: 25593-25602
  • DOI: 10.1074/jbc.m113.480574
  • Peer Reviewed
• [Journal Article] Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding. (2013)
  • Author(s): Kikuchi J, Shibayama N, Yamada S, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, Sugiyama K, Ohki M, Park SY, and Furukawa Y.
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Journal Article] BCR-ABL regulates death receptor expression for TNF-related apoptosis-inducing ligand (TRAIL) in Philadelphia chromosome-positive leukemia. (2013)
  • Author(s): Kuroda I, Inukai T, Zhang X, Kikuchi J, Furukawa Y, Nemoto A, Akahane K, Hirose K, Honna-Oshiro H, Goi K, Kagami K, Yagita H, Tauchi T, Maeda Y, Sugita K.
  • Journal Title: Oncogene Volume: 32 Pages: 1670-1681
  • Peer Reviewed
• [Journal Article] HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias. (2013)
  • Author(s): Calero-Nieto FJ, Joshi A, Bonadies N, Kinston S, Chan WI, Gudgin E, Pridans C, Landry JR, Kikuchi J, Huntly BJ, and Gottgens B.
  • Journal Title: Oncogene Volume: 32 Pages: 5471-5480
  • Peer Reviewed
• [Journal Article] Homopiperazine Derivatives as a Novel Class of Proteasome Inhibitors with a Unique Mode of Proteasome Binding. (2013)
  • Author(s): Kikuchi J.
  • Journal Title: PLoS One Volume: 8 Issue: 4 Pages: e60649-e60649
  • DOI: 10.1371/journal.pone.0060649
  • Peer Reviewed
• [Presentation] Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding (2013)
  • Author(s): Kikuchi J, Shibayama N, Yamada S, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, Sugiyama K, Ohki M, Park SY, and Furukawa Y
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2013-10-12
• [Presentation] Bortezomib overcomes the cell adhesion mediated drug resistance by down-regulating HDAC expression in multiple myeloma (2013)
  • Author(s): Furukawa Y, Kikuchi J
  • Organizer: 14^<th> International Myeloma Workshop
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2013-04-03
• [Presentation] Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding (2013)
  • Author(s): Kikuchi J, Shibayama N, Yamada S, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, Sugiyama K, Ohki M, Park SY, and Furukawa Y
  • Organizer: 14^<th> International Myeloma Workshop
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2013-04-03
• [Presentation] Bortezomib overcomes the cell adhesion-mediated drug resistance by down-regulating HDAC expression in multiple myeloma (2013)
  • Author(s): Furukawa Y, and Kikuchi J
  • Organizer: 14th International Myeloma Workshop
  • Place of Presentation: 京都
• [Presentation] Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding (2013)
  • Author(s): Kikuchi J, Shibayama N, Yamada S, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, Sugiyama K, Ohki M, Park SY, and Furukawa Y.
  • Organizer: 14th International Myeloma Workshop
  • Place of Presentation: 京都
• [Presentation] Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding (2013)
  • Author(s): Kikuchi J, Shibayama N, Yamada S, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, Sugiyama K, Ohki M, Park SY, and Furukawa Y.
  • Organizer: 第７５回 日本血液学会学術集会
  • Place of Presentation: 札幌
• [Remarks] ホームページ等, 難治性白血病に対する新規治療薬を発見しました
  • URL: http://www.jichi.ac.jp/news/research/2014/20140409.html
• [Remarks] ホームページ等, プロテアソーム阻害を介する新規抗がん剤を発見しました
  • URL: http://www.jichi.ac.jp/news/research/2014/20140403.html
• [Remarks] プロテアソーム阻害を介する新規抗がん剤を発見しました
  • URL: http://www.jichi.ac.jp/news/research/2014/20140403.html
• [Remarks] 難治性白血病に対する新規治療薬を発見しました
  • URL: http://www.jichi.ac.jp/news/research/2014/20140409.html