The role of micro RNA and histone modifiers in progression of myeloproliferative neoplasms

• Project/Area Number: 15K09484
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Fukushima Medical University
• Principal Investigator: Ikeda Kazuhiko 福島県立医科大学, 医学部, 准教授 (90381392)
• Co-Investigator(Kenkyū-buntansha): 小川 一英 福島県立医科大学, 医学部, 教授 (40423800)
• Co-Investigator(Renkei-kenkyūsha): Ueda Koki 福島県立医科大学, 医学部 血液内科学講座, 助教 (80632190)
• 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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: MPN / microRNA / histone / EZH2 / 骨髄増殖性腫瘍 / HMGA2 / let-7 / ポリコーム / 骨髄線維症

Outline of Final Research Achievements

Myeloproliferative neoplasms (MPNs) are characterized by activation of JAK-STAT pathway due to driver mutations including JAK2V617F, but some additional abnormalities may be necessary to maintain an MPN clone and advance the disease. The HMGA2, which acts as an oncogene by regulating expression of various genes, is frequently overexpressed due to downregulation of let-7 microRNAs and/or mutations in EZH2 in advanced MPN such as myelofibrosis. In mice with JAK2V617F, deletion of Ezh2 upregulates Hmga2. Correspondingly, overexpression of Hmga2 enhances splenomegaly and deteriorate anemia in mice carrying JAK2V617F, mimicking severe MPN. Therefore, Hmga2 may play an important role in progression of MPN.

Research Products

• [Int'l Joint Research] University of Pennsylvania(米国)
• [Journal Article] Hmga2 collaborates with JAK2 V617F in the development of myeloproliferative neoplasms (2017)
  • Author(s): Ueda K, Ikeda K, Ikezoe T, Harada-Shirado K, Ogawa K, Hashimoto Y, Sano T, Ohkawara H, Kimura S, Shichishima-Nakamura A, Nakamura Y, Shikama Y, Mori T, Mason PJ, Bessler M, Morishita S, Komatsu N, Shide K, Shimoda K, Koide S, Aoyama K, Oshima M, Iwama Aand Takeishi Y.
  • Journal Title: Blood Advances Volume: 1 Issue: 15 Pages: 1001-1015
  • DOI: 10.1182/bloodadvances.2017004457
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Amelioration of Myelofibrosis with Thrombocytopenia by a JAK1/2 Inhibitor, Ruxolitinib, in a Post-polycythemia Vera Myelofibrosis Patient with a <i>JAK2</i> Exon 12 Mutation (2017)
  • Author(s): Kazuhiko Ikeda, Koki Ueda, Takahiro Sano, Kazuei Ogawa, Takayuki Ikezoe, Yuko Hashimoto, Soji Morishita, Norio Komatsu, Hitoshi Ohto, Yasuchika Takeishi
  • Journal Title: Internal Medicine Volume: 56 Issue: 13 Pages: 1705-1710
  • DOI: 10.2169/internalmedicine.56.7871
  • NAID: 130006858099
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Mechanisms of Impaired Neutrophil Migration by MicroRNAs in Myelodysplastic Syndromes. (2017)
  • Author(s): Cao M, Shikama Y, Kimura H, Noji H, Ikeda K, Ono T, Ogawa K, Takeishi Y, Kimura J
  • Journal Title: J.Immunol. Volume: 198(5) Issue: 5 Pages: 1887-1899
  • DOI: 10.4049/jimmunol.1600622
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Steroid-resistant autoimmune myelofibrosis in a patient with autoimmune hepatitis and Evans syndrome complicated with increased expression of TGF-β in the bone marrow: a case report (2017)
  • Author(s): Hiroshi Ohkawara, Miki Furukawa, Kazuhiko Ikeda, Akiko Shichishima-Nakamura, Masahiko Fukatsu, Takahiro Sano, Koki Ueda, Satoshi Kimura, Risa Kanai, Yuka Oka, Fumi Murakami, Osamu Suzuki, Yuko Hashimoto, Kazuei Ogawa, Takayuki Ikezoe
  • Journal Title: International Journal of Hematology Volume: 106 Issue: 5 Pages: 718-724
  • DOI: 10.1007/s12185-017-2268-3
  • Peer Reviewed / Open Access
• [Journal Article] MPN診断の実際～WHO2016基準を中心に. (2017)
  • Author(s): 池田 和彦
  • Journal Title: 最新医学 Volume: 72 Pages: 1552-1557
• [Journal Article] Autocrine and Paracrine Interactions between Multiple Myeloma Cells and Bone Marrow Stromal Cells by Growth Arrest-specific Gene 6 Cross-talk with Interleukin-6. (2017)
  • Author(s): Furukawa M, Ohkawara H, Ogawa K, Ikeda K, Ueda K, Shichishima-Nakamura A, Ito E, Imai JI, Yanagisawa Y, Honma R, Watanabe S, Waguri S, Ikezoe T, Takeishi Y
  • Journal Title: The Journal of biological chemistry Volume: 292 Issue: 10 Pages: 4280-4292
  • DOI: 10.1074/jbc.m116.733030
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ruxolitinib treatment for graft-versus-host disease in patients with myelofibrosis (2016)
  • Author(s): Yasuo Mori, Kazuhiko Ikeda, Tomoko Inomata, Goichi Yoshimoto, Nobuharu Fujii, Hiroatsu Ago, Takanori Teshima
  • Journal Title: Bone Marrow Transplant Volume: 51 Issue: 12 Pages: 1584-1587
  • DOI: 10.1038/bmt.2016.256
  • Peer Reviewed
• [Journal Article] 骨髄増殖性腫瘍における分子病態研究の最前線 (2016)
  • Author(s): 池田和彦
  • Journal Title: 臨床血液 Volume: 57 Pages: 156-164
  • NAID: 130005132717
  • Peer Reviewed
• [Journal Article] Reduction of c-Fos via Overexpression of miR-34a Results in Enhancement of TNF- Production by LPS in Neutrophils from Myelodysplastic Syndrome Patients. (2016)
  • Author(s): Shikama Y, Cao M, Ono T, Feng X, Noji H, Kimura H, Ogawa K, Suzuki Y, Ikeda K, Takeishi Y, Kimura J.
  • Journal Title: PLoS One Volume: 11 Issue: 8 Pages: e0158527-e0158527
  • DOI: 10.1371/journal.pone.0158527
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recent advances in molecular pathogenesis of myeloproliferative neoplasms (2016)
  • Author(s): 池田和彦
  • Journal Title: Rinsho Ketsueki Volume: 57 Issue: 2 Pages: 156-164
  • DOI: 10.11406/rinketsu.57.156
  • NAID: 130005132717
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] CD4+ T cells in aged or thymectomized recipients of allogeneic stem cell transplantations. (2015)
  • Author(s): Takahashi H, Ikeda K, Ogawa K, Saito S, Ngoma AM, Mashimo Y, Ueda K, Furukawa M, Shichishima-Nakamura A, Ohkawara H, Nollet KE, Ohto H, Takeishi Y.
  • Journal Title: Biological Research Volume: 48 Issue: 1 Pages: 41-41
  • DOI: 10.1186/s40659-015-0033-8
  • Peer Reviewed / Open Access
• [Presentation] 骨髄増殖性腫瘍のさらなる診断向上に向けて (2017)
  • Author(s): 池田和彦
  • Organizer: 日本病理学会
  • Place of Presentation: 東京
  • Year and Date: 2017-04-28
  • Invited
• [Presentation] 骨髄線維症におけるHMGA2発現とポリコーム抑制複合体2関連遺伝子変異 (2017)
  • Author(s): 池田和彦，植田航希，原田佳代，七島晶子，大河原浩，池添隆之
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] 骨髄増殖性腫瘍の更なる診断向上に向けて (2017)
  • Author(s): 池田和彦
  • Organizer: 第106回日本病理学会総会
  • Invited
• [Presentation] Functional Impairment of Hematopoietic Stem/Progenitor Cells By Loss of Uhrf2 in Mice. (2017)
  • Author(s): Sano T, Ueda K, Ikeda K, Ogawa K, Mori T, Ikezoe T.
  • Organizer: American Society of Hematology
  • Int'l Joint Research
• [Presentation] HMGA2 orchestrates the tumorgenesis of myeloproliferative neoplasms (MPN) in corporation with JAK2V617F (2016)
  • Author(s): Ueda K, Ikeda K, Ikezoe T, Ogawa K, Hashimoto Y, Harada-Shirado K, Ohkawara H, Komatsu N, Shide K, Shimoda K, Koide S, Oshima M, Iwama A, Takeishi Y.
  • Organizer: 58th American Society of Hematology (ASH) Annual Meeting and Exposition
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] 真性多血症の治療の観点から (2016)
  • Author(s): 池田和彦
  • Organizer: 第78回 日本血液学会学術集会, 横浜
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
  • Invited
• [Presentation] Expression of HMGA2 Collaborates with JAK2V617F to Progress Myeloproliferative Neoplasms (2015)
  • Author(s): Ueda K, Ikeda K, et al.
  • Organizer: American Society of Hematology
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-12-07
  • Int'l Joint Research
• [Book] 骨髄線維症 (MF) -分子病態の解明から新規薬物治療薬の開発まで- 小松則夫 編 (2016)
  • Author(s): 池田和彦
  • Total Pages: 6
  • Publisher: 医薬ジャーナル社