The role of HMGA2 in expansion of an abnormal hematopoietic clone

• Project/Area Number: 24591405
• 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): TAKEISHI Yasuchika 福島県立医科大学, 医学部, 教授 (40272067) ; OGAWA Kazuei 福島県立医科大学, 医学部, 教授 (40423800)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 骨髄増殖性腫瘍 / 原発性骨髄線維症 / HMGA2 / マイクロRNA / エピジェネティックス / HMGA2高発現 / DNAメチル化 / 病態進展 / 国際情報交換 / 骨髄性腫瘍

Outline of Final Research Achievements

Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia and primary myelofibrosis (PMF), are clonal hematological disorders characterized by proliferation of mature blood cells. In this study, we found deregulated HMGA2 mRNA expression due to reduced let-7 micro RNA (miRNAs) in granulocytes from patients with almost all of PMF and over 20% of PV and ET, being associated with splenomegaly, elevated serum LDH values, and methylation of p16 promoter. Since association of histone deacetylase (HDAC) with HMGA2 has been reported in cord blood-derived cells, we next studied effects of an HDAC inhibitor panobinostat on expressions of HMGA2 and let-7 in HMGA2-expressing myeloid cells including PMF-derived CD34+ cells. The panobinostat decreased expression of HMGA2 through 3’UTR of HMGA2 mRNA by increasing expressions of let-7 miRNAs. Thus, deregulated expression of HMGA2 due to downregulation of let-7 miRNAs is a possible therapeutic target of HDACi in MPNs.

Research Products

• [Journal Article] Dysregulation of the MIRLET7/HMGA2 axis with methylation of the CDKN2A promoter in myeloproliferative neoplasms. (2015)
  • Author(s): Harada-Shirado K, Ikeda K, Ogawa K, Ohkawara H, Kimura H, Kai T, Noji H, Morishita S, Komatsu N, Takeishi Y.
  • Journal Title: Brit J Haematol. Volume: 168 Issue: 3 Pages: 338-349
  • DOI: 10.1111/bjh.13129
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] High mobility group box 1 promotes angiogenesis from bone marrow- derived endothelial progenitor cells after myocardial infarction. (2015)
  • Author(s): Nakamura Y, Suzuki S, Shimizu T, Miyata M, Ikeda K, Saitoh S, Kubota I, Takeishi Y.
  • Journal Title: J Atheroscler Thromb. Volume: 0 Pages: 0-0
  • NAID: 130005078031
  • Peer Reviewed
• [Journal Article] Multicentric Castleman's disease with impaired lymphocytic apoptosis (2015)
  • Author(s): Minemura H, Ikeda K, Tanino Y, Hashimoto Y, Nikaido T, Fukuhara A, Yokouchi H, Sato S, Tanino M, Oka T, Hebisawa A, Suzuki H, Ogawa K, Takeishi Y, Munakata M.
  • Journal Title: Allergology International Volume: 64 Issue: 1 Pages: 112-114
  • DOI: 10.1016/j.alit.2014.08.009
  • NAID: 130004873132
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed
• [Journal Article] Membrane type 1-matrix metalloproteinase/Akt signaling axis modulates TNF-α-induced procoagulant activity and apoptosis in endothelial cells (2014)
  • Author(s): Ohkawara H, Ishibashi T, Sugimoto K, Ikeda K, Ogawa K, Takeishi Y
  • Journal Title: PLoS One Volume: 9 Issue: 8 Pages: e105697-e105697
  • DOI: 10.1371/journal.pone.0105697
  • Peer Reviewed / Open Access
• [Journal Article] Anti-Influenza Viral Agent Peramivir Possibly Elicited Severe Immune Thrombocytopenia. (2014)
  • Author(s): Harada-Shirado K, Ikeda K*, Furukawa M, Sukegawa M, Takahashi H, Shichishima-Nakamura A, Noji H, Kawabata K, Saito S, Ohto H, Ogawa K, Takeishi Y.
  • Journal Title: Intern Med Volume: 53 Pages: 1549-1552
  • Peer Reviewed / Open Access
• [Journal Article] 骨髄増殖性腫瘍におけるHMGA2 (high mobility group AT-hook2) の役割. (2014)
  • Author(s): 池田和彦
  • Journal Title: 血液フロンティア Volume: 24 Pages: 997-1003
• [Journal Article] マイクロRNAと血液疾患：エピジェネティクス（クロマチン制御）とマイクロRNA. (2014)
  • Author(s): 池田和彦
  • Journal Title: 血液内科 Volume: 68 Pages: 742-746
• [Journal Article] Molecular response of e19a2 BCR-ABL1 chronic myeloid leukemia with double Philadelphia chromosome by dasatinib (2014)
  • Author(s): Ikeda K, Harada-Shirado K, Matsumoto H, Noji H, Ogawa K, Takeishi Y.
  • Journal Title: J Clin Oncol Volume: In press
  • Peer Reviewed
• [Journal Article] Peripheral blood progenitor cell collection by two programs for autologous and allogeneic transplantation. (2014)
  • Author(s): Ikeda K, Ohto H, Kanno T, Gonda K, Suzuki Y, Ono T, Saito S, Takahashi H, Kimura S, Harada-Shirado K, Yamauchi H, Hoshino Y, Mashimo Y, Nollet KE, Kikuta A, Ogawa K, Takeishi Y.
  • Journal Title: Transfusion Volume: In press
  • Peer Reviewed
• [Journal Article] Somatic 15q break after long-term stable disease in acute myeloid leukemia (2014)
  • Author(s): Harada-Shirado K, Ikeda K, Matsumoto H, Shiga Y, Furukawa M, Takahashi H, Ohkawara H, Noji H, Hashimoto Y, Waguri S, Watanabe S, Ogawa K, Takeishi Y
  • Journal Title: Clinical Lymphoma, Myeloma & Leukemia Volume: 14 Issue: 2 Pages: e69-e72
  • DOI: 10.1016/j.clml.2013.10.009
  • Peer Reviewed / Open Access
• [Journal Article] A new method for maturity-dependent fractionation of neutrophil progenitors applicable for the study of myelodysplastic syndromes. (2014)
  • Author(s): Hu H, Shikama Y, Shichishima T, Ikeda K, Akutsu K, Ono T, Kimura H, Ogawa K, Noji H, Takeishi Y, Kimura J.
  • Journal Title: Biomark Res. Volume: 2 Issue: 1 Pages: 1-3
  • DOI: 10.1186/2050-7771-2-2
  • Peer Reviewed / Open Access
• [Journal Article] A case of pleural solitary fibrous tumor complicated with autoimmune hemolytic anemia. (2014)
  • Author(s): Takahashi H, Ohkawara H, Ikeda K, et al.
  • Journal Title: Intern Med Volume: In press
  • Peer Reviewed
• [Journal Article] Impairment of FOS mRNA stabilization following translation arrest in granulocytes from myelodysplastic syndrome patients. (2013)
  • Author(s): Feng X, Shikama Y, Shichishima T, Noji H, Ikeda K, Ogawa K, Kimura H, Takeishi Y, Kimura J.
  • Journal Title: PLOS One Volume: 8
• [Journal Article] Maturity-dependent fractionation of neutrophil progenitors: A new method to examine in vivo expression profiles of differentiation-regulating genes (2012)
  • Author(s): Hu H, Shikama Y, Shichishima T, Ikeda K, Akutsu K, Ono T, Kimura H, Ogawa K, Noji H, Takeishi Y, Kimura J
  • Journal Title: ExpHematol Volume: 40(8) Issue: 8 Pages: 675-681
  • DOI: 10.1016/j.exphem.2012.03.003
  • Peer Reviewed
• [Journal Article] A Japanese case of chronic lymphocytic leukemia with t(1;6) (2012)
  • Author(s): Harada K, Ikeda K, Matsumoto H, Furukawa M, Takahashi H, Ohkawara H, Noji H, Tasaki K, Abe M, Ogawa K, Takeishi Y
  • Journal Title: Exp Hematol Oncol Volume: 1 (1) Issue: 1 Pages: 28-28
  • DOI: 10.1186/2162-3619-1-28
  • Peer Reviewed
• [Journal Article] The role of HMGA2 in the proliferation and expansion of a hematopoietic cell in myeloproliferative neoplasms. (2012)
  • Author(s): Ikeda K, Ogawa K, Takeishi Y.
  • Journal Title: Fukushima J Med Sci. Volume: 58 Pages: 91-100
  • NAID: 130002566788
  • Peer Reviewed
• [Journal Article] 骨髄増殖性腫瘍の分子病態 -High mobility group AT-hook 2 (HMGA2) の役割- (2012)
  • Author(s): 池田和彦
  • Journal Title: 日本輸血細胞治療学会誌 Volume: 58 Pages: 441-447
  • NAID: 10030828900
  • Peer Reviewed
• [Presentation] 骨髄増殖性腫瘍におけるHMGA2高発現の役割 (2015)
  • Author(s): 池田和彦、原田佳代、小川一英、小松則夫、竹石恭知
  • Organizer: 日本臨床分子医学会
  • Place of Presentation: 京都
  • Year and Date: 2015-04-10 – 2015-04-11
• [Presentation] High mobility group box 1 promotes angiogenesis from bone marrow-derived endothelial progenitor cells after myocardial infarction (2014)
  • Author(s): Nakamura Y, Suzuki S, Shimizu T, Miyata M, Shishido T, Ikeda K, Saitoh S, Kubota I, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2014
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Neutrophilia and ineffective erythropoiesis in old mice overexpressing Hmga2 (2014)
  • Author(s): Ikeda K, Mason P, Harada-Shirado K, Ogawa K, Bessler M, Takeishi Y
  • Organizer: 第76回 日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Correlation of HMGA2 mRNA and let-7 micro RNAs with Methylation of p16 in MPNs (2014)
  • Author(s): Harada-Shirado K, Ikeda K, Ogawa K, Noji H, Ohkawara H, Kimura H, kai T, Morishita S, Komatsu N, Takeishi Y
  • Organizer: 第76回 日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] The role of deregulated HMGA2 expression due to repressed let-7 micro RNA in myeloproliferative neoplasm (MPNs) (2014)
  • Author(s): Harada-Shirado K, Ikeda K, Ogawa K, Noji H, Ohkawara H, Kimura H, Kai T, Morishita S, Komatsu N, Takeishi Y
  • Organizer: The 5th JSH International Symposium
  • Place of Presentation: Hamamatsu, Japan
  • Year and Date: 2014-05-24 – 2014-05-25
• [Presentation] PNHクローンの拡大機序
  • Author(s): 池田和彦
  • Organizer: Japan PNH Masters
  • Place of Presentation: 東京
  • Invited
• [Presentation] Expression of let-7 micro RNAs in transgenic ΔHmga2 mice
  • Author(s): Ikeda K, Harada K, Ogawa K, Mason P, Bessler M, Takeishi Y
  • Organizer: 第74回 日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Expression of let-7 micro RNAs in transgenic mice overexpressing truncated Hmga2
  • Author(s): Ikeda K, Harada K, Ogawa K, Mason PJ, Bessler M, Takeishi Y
  • Organizer: 2012 American Society of Hematology (ASH) Annual Meeting and Exposition
  • Place of Presentation: 米国ジョージア州アトランタ