Role of glucose metabolism in development of myelofibrosis

• Project/Area Number: 15K09470
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Yamanashi
• Principal Investigator: KIRITO Keita 山梨大学, 大学院総合研究部, 教授 (90306150)
• Co-Investigator(Kenkyū-buntansha): 川島 一郎 山梨大学, 大学院総合研究部, 助教 (20622369) ; 三森 徹 山梨大学, 大学院総合研究部, 講師 (80377514) ; 野崎 由美 山梨大学, 総合研究部, 助教 (80530104)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: myelofibrosis / JAK2V617F / metformin / lysyl oxidase / PP2A / 線維化 / ERストレス / Lysyl oxidase / 骨髄増殖性腫瘍 / 糖代謝 / 活性酸素 / 低酸素 / 骨髄線維化 / 乳酸 / MCT

Outline of Final Research Achievements

In the present study, we focused our attention on the role of microenvironment and cell to cell interaction to understand the mechanisms for development of myelofibrosis in myeloproliferative neoplasms (MPN). We found that JAK2V617F-positive cell lines derived from MPN patients showed elevation of several ER stress markers including phosphorylation of eIF2-alpha, nuclear localization of ATF6 and XBP1s and upregulation of glucose response protein 78. We also confirmed elevation of Lysyl-oxidase (LOX), an enzyme that regulates the crosslinking of extracellular matrix proteins such as collagen in these cells. Treatment with metformin diminished activation of ER stress pathways and suppressed LOX levels. These results indicated that LOX levels were regulated by ER stress in MPN cells. In addition, it is suggested that metformin might be a new and attractive compounds to suppress myelofibrosis in MPN.

Research Products

• [Journal Article] Effect of ruxolitinib therapy on the quality-of-life of Japanese patients with myelofibrosis (2018)
  • Author(s): Oritani K, Ohishi K, Okamoto S, Kirito K, Komatsu N, Tauchi T, Handa H, Saito S, Takenaka K, Shimoda K, Okada H, Amagasaki T, Wakase S, Shimozuma K, Akashi K
  • Journal Title: Current Medical Research and Opinion Volume: 34 Pages: 531-537
  • DOI: 10.1080/03007995.2017.1415874
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of the dose and efficacy of ruxolitinib in Japanese patients with myelofibrosis (2018)
  • Author(s): Kirito K, Okamoto S, Ohishi K, Tauchi T, Handa H, Saito S, Takenaka K, Shimoda K, Oritani K, Akashi K, Okada H, Amagasaki T, Suzuki K, Yonezu T, Komatsu N
  • Journal Title: Int J Hematol. Volume: 107(1) Pages: 92-97
  • DOI: 10.1007/s12185-017-2332-z
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Efficacy and Safety of First-Line Dasatinib Therapy and the Relevance of Velocity of BCR-ABL1 Transcript Decline for Achievement of Molecular Responses in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Report from the Juntendo Yamanashi Cooperative Study Group (2017)
  • Author(s): Takaku Tomoiku、Iriyama Noriyoshi、Mitsumori Toru、Sato Eriko、Gotoh Akihiko、Kirito Keita、Noguchi Masaaki、Koike Michiaki、Sakamoto Junichi、Oba Koji、Komatsu Norio
  • Journal Title: Oncology Volume: 94 Pages: 85-91
  • DOI: 10.1159/000481945
  • Peer Reviewed
• [Journal Article] Ruxolitinib is effective and safe in Japanese patients with hydroxyurea-resistant or hydroxyurea-intolerant polycythemia vera with splenomegaly (2017)
  • Author(s): Kirito Keita、Suzuki Kenshi、Miyamura Koichi、Takeuchi Masahiro、Handa Hiroshi、Okamoto Shinichiro、Gadbaw Brian、Yamauchi Kyosuke、Amagasaki Taro、Ito Kazuo、Hino Masayuki
  • Journal Title: International Journal of Hematology Volume: 107 Pages: 173-184
  • DOI: 10.1007/s12185-017-2333-y
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Metformin inhibits JAK2V617F activity in MPN cells by activating AMPK and PP2A complexes containing the B56alpha subunit (2016)
  • Author(s): Kawashima I, Kirito K
  • Journal Title: Experimental Hematology Volume: 44 Pages: 1156-1165
  • DOI: 10.1016/j.exphem.2016.08.005
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cells (2015)
  • Author(s): Kawashima, I. Mitsumori, T. Nozaki, Y. Yamamoto, T. Shobu-Sueki, Y. Nakajima, K. Kirito, K.
  • Journal Title: Exp Hematol Volume: in press
  • DOI: 10.1016/j.exphem.2015.03.005
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Aberrant Activation of NF-κB and Hypoxia Enhances Glycolytic Enzyme Hexokinase II Expression in B-Cell Lymphoma through Activation of HIF-1 (2017)
  • Author(s): Nakajima, Kei Kirito, Keita Kawashima, Ichiro Koshiishi, Megumi Kumagai, Takuma Mitsumori, Toru
  • Organizer: 第５９回米国血液学会
• [Presentation] Metformin Inhibits JAK2V617F Activity By Activating AMPK and PP2A Containing B56 Alpha Subunits in MPN Cells (2015)
  • Author(s): Ichiro kawashima, Keita Kirito
  • Organizer: 57th ASH Annual Meeting and Exposition
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] Metformin inhibits the growth of JAK2V617F-harboring cells through direct inhibition of JAK2V617F (2015)
  • Author(s): Ichiro kawashima, Keita Kirito
  • Organizer: 第77回日本血液学会
  • Place of Presentation: 石川県金沢市
  • Year and Date: 2015-10-06
• [Remarks] 山梨大学医学部血液・腫瘍内科 ホームページ内： 臨床研究の結果が論文として発表されました。
  • URL: http://www.yamanashi-hematology.com/modules/information/index.php?page=article&storyid=196
• [Remarks] 山梨大学医学部血液・腫瘍内科 ホームページ内： 臨床研究の結果が掲載されました。
  • URL: http://www.yamanashi-hematology.com/modules/information/index.php?page=article&storyid=193
• [Remarks] 山梨大学医学部血液・腫瘍内科 ホームページ内： 論文が受理されました。
  • URL: http://www.yamanashi-hematology.com/modules/information/index.php?page=article&storyid=192
• [Remarks] 山梨大学医学部血液・腫瘍内科 ホームページ内： 論文が受理されました。
  • URL: http://www.yamanashi-hematology.com/modules/information/index.php?page=article&storyid=191
• [Remarks] 研究論文がExperimental Hematologyに受理されました。
  • URL: http://www.yamanashi-hematology.com/modules/information/index.php?page=article&storyid=183
• [Remarks] 研究成果の発表
  • URL: http://www.yamanashi-hematology.com/
• [Funded Workshop] 第５９回米国血液学会 (2017)
• [Funded Workshop] 第５８回米国血液学会年次総会 (2016)
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2016-12-03