Molecular mechanism of treatment-resistant symptoms in myelofibrosis

• Project/Area Number: 26860738
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: University of Miyazaki
• Principal Investigator: Shide Kotaro 宮崎大学, 医学部, 助教 (20468028)
• Co-Investigator(Renkei-kenkyūsha): KAMEDA Takuro 宮崎大学, 医学部, 医員 (30468029)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 骨髄線維症 / 分子標的治療

Outline of Final Research Achievements

For the treatment of primary myelofibrosis and post-PV, post-ET myelofibrosis, the small molecule inhibitors of JAK2 have shown a remarkable therapeutic effect. The drugs are very effective in splenomegaly and constitutional symptoms, on the other hand have no effect on bone marrow fibrosis and anemia. In this study, we studied the molecular mechanisms of these refractory symptoms using JAK2 V617F transgenic mice. (1) Bone marrow fibrosis: We identified that JAK2 mutation activates MEK-ERK1/2 pathway downstream of MPL and may contribute to TGFβ1 overproduction, causing bone marrow fibrosis via transcriptional enhancement of USF1, and MEK inhibition improve bone marrow fibrosis. (2)Anemia and drug resistance: We showed that TYK2 defects does not affect the anemia or inhibitor resistance of the transgenic mice. (3)The role of epigenetic abnormality: We identified that loss of TET2 accelerates the degree of malignancy and sustains MPNs in combination with JAK2V617F.

Research Products

• [Journal Article] 骨髄増殖性腫瘍におけるTET2欠損の意義 (2016)
  • Author(s): 亀田拓郎, 幣光太郎
  • Journal Title: 血液内科 Volume: 72 Pages: 220-224
• [Journal Article] Loss of TET2 has dual roles in murine myeloproliferative neoplasms: disease sustainer and disease accelerator. (2015)
  • Author(s): Kameda T, Shide K, Yamaji T, Kamiunten A, Sekine M, Taniguchi Y, Hidaka T, Kubuki Y, Shimoda H, Marutsuka K, Sashida G, Aoyama K, Yoshimitsu M, Harada T, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Yamamoto S, Hasuike S, Nagata K, Iwama A, Kitanaka A, Shimoda K.
  • Journal Title: Blood Volume: 125 Issue: 2 Pages: 304-315
  • DOI: 10.1182/blood-2014-04-555508
  • NAID: 40020613861
  • Peer Reviewed / Open Access
• [Journal Article] Gene expression profiling of loss of TET2 and/or JAK2V617F mutant hematopoietic stem cells from mouse models of myeloproliferative neoplasms. (2015)
  • Author(s): Kameda T, Shide K, Yamaji T, Kamiunten A, Sekine M, Hidaka T, Kubuki Y, Sashida G, Aoyama K, Yoshimitsu M, Abe H, Miike T, Iwakiri H, Tahara Y, Yamamoto S, Hasuike S, Nagata K, Iwama A, Kitanaka A, Shimoda K
  • Journal Title: Genom Data. Volume: 4 Pages: 102-108
  • DOI: 10.1016/j.gdata.2015.04.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional analysis of TET2 using a knockdown mouse model (2015)
  • Author(s): 幣光太郎、亀田拓郎、下田和哉
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 6 Pages: 657-665
  • DOI: 10.11406/rinketsu.56.657
  • NAID: 130005093100
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Genetic and epigenetic abnormalities in myeloproliferative neoplasms (2015)
  • Author(s): 亀田拓郎、幣光太郎、下田和哉
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 6 Pages: 614-622
  • DOI: 10.11406/rinketsu.56.614
  • NAID: 130005093094
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Molecularly pathogenesis and molecular targeted therapy for myeloproliferative neoplasms (2015)
  • Author(s): Shide K.
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 2 Pages: 150-158
  • DOI: 10.11406/rinketsu.56.150
  • NAID: 130004920713
  • ISSN: 0485-1439, 1882-0824
• [Journal Article] 骨髄線維症におけるドライバー変異の臨床的意義 (2015)
  • Author(s): 幣光太郎, 下田和哉
  • Journal Title: 血液内科 Volume: 71 Pages: 511-515
  • NAID: 40020643106
• [Journal Article] Beyond JAK inhibitors. (2015)
  • Author(s): .幣光太郎, 下田和哉
  • Journal Title: 血液内科 Volume: 70 Pages: 171-175
• [Journal Article] 骨髄増殖性腫瘍の異常造血幹細胞 (2014)
  • Author(s): 幣光太郎, 亀田拓郎
  • Journal Title: 血液フロンティア Volume: 24 Pages: 1005-1013
• [Journal Article] MPNの分子病態解明研究の進歩 (2014)
  • Author(s): 幣光太郎
  • Journal Title: 血液内科 Volume: 69 Pages: 214-220
• [Presentation] Expression of HMGA2 Collaborates with JAK2V617F to Progress Myeloproliferative Neoplasms (2015)
  • Author(s): Koki Ueda, Kazuhiko Ikeda, Kazuei Ogawa, Akiko Shichishima-Nakamura, Kotaro Shide, Kazuya Shimoda, Yuko Hashimoto, Philip J Mason, Monica Bessler and Yasuchika Takeishi
  • Organizer: American Society of Hematology 57th Annual Meeting
  • Place of Presentation: Orlando FL, 米国
  • Year and Date: 2015-12-07
  • Int'l Joint Research
• [Presentation] Importance of bone marrow (BM) biopsy for diagnosing polycythemia vera (PV) in clinical practice (2015)
  • Author(s): Takuro Kameda, Kotaro Shide, Ayako Kamiunten, Masaaki Sekine, Keiichi Akizuki, Haruko, Shimoda, Tomonori Hidaka, Youko Kubuki, Akira Kitanaka, Kazuya Shimoda
  • Organizer: 第77回日本血液学会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-17
• [Presentation] αSMA+ macrophages skewed from HSCs by vitamin D3 initiate myelofibrosis with osteosclerosis (2015)
  • Author(s): Kanako Wakahashi, Kentaro Minagawa, Noboru Asada, Yuko Kawano, Mari Sato, Hiroki Kawano, Akiko Sada, Shigeaki Kato, Kotaro Shide, Kazuya Shimoda, Toshimitsu Matsui, Yoshio Katayama
  • Organizer: 第77回日本血液学会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-17
• [Presentation] Therapies targeting the MAPK pathway improve bone marrow (BM) fibrosis induced by JAK2V617F(JAK2VF) (2015)
  • Author(s): Kotaro Shide, Takuro Kameda, Ayako Kamiunten, Masaaki Sekine, Keiichi Akizuki, Haruko, Shimoda, Tomonori Hidaka, Youko Kubuki, Akira Kitanaka, Kazuya Shimoda
  • Organizer: 第77回日本血液学会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] Therapies Targeting the MAPK Pathway Improve Bone Marrow (BM) Fibrosis Induced By JAK2V617F (2014)
  • Author(s): Shide K, Kameda T, Kamiunten A, Sekine M, Akizuki K, Shimoda H, Hidaka T, Kubuki Y, Kitanaka A, Shimoda K
  • Organizer: American Society of Hematology 56th Annual Meeting
  • Place of Presentation: San Francisco CA, 米国
  • Year and Date: 2014-12-07
• [Presentation] Loss-of-TET2 induces clonal expansion of JAK2V617F mutant stem/progenitor cells and initiates MPNs (2014)
  • Author(s): Kameda T, Shide K, Akizuki K, Sekine M, Kamiunten A, Shimoda H, Hidaka T, Kubuki Y, Kitanaka A, Marutsuka K, Shimoda K
  • Organizer: 第76回日本血液学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31
• [Presentation] CALR mutation and clinical correlates in myeloproliferative neoplasms (2014)
  • Author(s): Shide K, Kameda T, Kamiunten A, Sekine M, Akizuki K, Shimoda H, Hidaka T, Kubuki Y, Kitanaka A, Shimoda K
  • Organizer: 第76回日本血液学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31
• [Book] Annual Review 2016 血液 高久史麿, 小澤敬也, 金倉譲, 小島勢二, 矢冨裕 編 (2016)
  • Author(s): 亀田拓郎, 幣光太郎
  • Publisher: 中外医学社
• [Patent(Industrial Property Rights)] 骨髄線維化の抑制剤 (2015)
  • Inventor(s): 幣光太郎、下田和哉
  • Industrial Property Rights Holder: 宮崎大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-016390
  • Filing Date: 2015-01-30