Analysis of leukemogenic mechanisms by deregulated expression of histone demethylase Fbxl10

• Project/Area Number: 23390252
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Hiroshima University
• Principal Investigator: HONDA Hiroaki 広島大学, 原爆放射線医科学研究所, 教授 (40245064)
• Co-Investigator(Kenkyū-buntansha): INABA Toshiya (60281292) ; UEDA Takeshi 広島大学, 原爆放射線医科学研究所, 助教 (60585149) ; HONDA Zen-ichiro お茶の水女子大学, 保健管理センター, 教授 (70238814)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2012: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2011: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: ヒストン脱メチル化酵素 / Fbxl10 / トランスジェニックマウス / 白血病 / 造血幹細胞 / Fbx110

Research Abstract

We generated transgenic mice that overexpress Fbxl10, a histone demethylase, in hematopoietic stem cells (HSCs), and found that the mice develop leukemia at about 1 year after birth. By bone marrow transplantation, we demonstrated that the leukemia was caused by enhanced HSC-intrinsic proliferative potentials. In addition, we found that neuron specific gene 2 (Nsg2), which encodes a protein involved in intracellular transport, was overexpressed and that genes involved in oxidative phosphorylation in mitochondria were significantly up-regulated. Our findings provide novel insights in the leukemogenic mechanisms from the viewpoint of energy metabolism and intracellular transport.

Research Products

• [Journal Article] The IL-2/CD25 Axis Maintains Distinct Subsets of Chronic Myeloid Leukemia–Initiating Cells. (2014)
  • Author(s): Kobayashi CI, Takubo K, Kobayashi H, Nakamura-Ishizu A, Honda H, Kataoka K, Kumano K, Akiyama H, Sudo T, Kurokawa M, Suda T
  • Journal Title: Blood Volume: 123 Pages: 2540-2549
  • Peer Reviewed
• [Journal Article] A long lasting puzzle for －7/7q－ syndrome. (2014)
  • Author(s): Honda H, Inaba T
  • Journal Title: Oncotarget Volume: 5 Pages: 7-8
  • Peer Reviewed
• [Journal Article] Acquired deficiency of A20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function (2014)
  • Author(s): Nagamachi A, Nakata Y, Ueda T, Yamasaki N, Ebihara Y, Tsuji K, Honda Zi, Takubo K, Suda T, Oda H, Inaba T, Honda H
  • Journal Title: PLoS One. Volume: 9 Pages: 1-10
  • DOI: 10.1371/journal.pone.0087425
  • Peer Reviewed / Open Access
• [Journal Article] Haploinsufficiency of SAMD9L, an endosome fusion facilitator, in mice induces the development of myeloid malignancies mimicking human diseases with monosomy 7. (2014)
  • Author(s): Nagamachi A
  • Journal Title: Cancer Cell. Volume: 24 Pages: 305-17
  • DOI: 10.1016/j.ccr.2013.08.011
  • Peer Reviewed
• [Journal Article] CIZ1, a p21 Cip1 /Waf1-interacting protein, functions as a tumor suppressor in vivo (2013)
  • Author(s): Nishibe R, Watanabe W, Ueda T, Yamasaki N, Koller R, Wolff L, Honda Z-i, Ohtsubo M, Honda H
  • Journal Title: FEBS Lett Volume: 587 Pages: 1529-1535
  • Peer Reviewed
• [Journal Article] p130Cas plays important roles in osteoclastic bone resorption (2013)
  • Author(s): Nagai Y, Osawa K, Fukushima H, Tamura Y, Aoki K, Ohya K, Yasuda H, Hikiji H, Seta Y, Seo S, Kurokawa M, Kato S, Honda H, Nakamura I, Maki K, Jimi E
  • Journal Title: J Bone Miner Res Volume: 28(12) Pages: 2449-62
  • Peer Reviewed
• [Journal Article] Skeletal muscle adaptation 1 in response to mechanical stress in p130Cas-/- mice (2013)
  • Author(s): Akimoto T, Okuhira K, Aizawa K, Wada S, Honda H, Fukubayashi T, Uchida T
  • Journal Title: Am J Physiol Cell Physiol Volume: 304
• [Journal Article] Induction of pluripotent stem cells from primordial germ cells by single reprogramming factors (2013)
  • Author(s): Nagamatsu G. Kosaka T, Saito S, Honda H, Takubo K, Kinoshita T, Akiyama H, Sudo T, Horimoto K, Oya M, Suda T
  • Journal Title: Stem Cells Volume: 31 Pages: 479-487
  • Peer Reviewed
• [Journal Article] EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms (2012)
  • Author(s): Ueda T, Sanada M, Matsui H, Yamasaki N, Honda Zi, Shih LY, Mori H, Inaba T, Ogawa S, Honda H
  • Journal Title: Leukemia Volume: 26 Pages: 2557-2560
  • Peer Reviewed
• [Journal Article] Oncogenic fusion E2A-HLF sensitizes t(17;19)-positive acute lymphoblastic leukemia to TRAIL-mediated apoptosis by upregulating the expression of death receptors (2012)
  • Author(s): Zhang X, Kinuko Hirose K, Akahane K, Kuroda I, Honna H, Kagami K, Goi K, Nakamura K, Kobayashi M, Yagita H, Kurosawa H, Look AT, Honda H, Inaba T, Nakazawa S, Sugita K, Endo M, Inukai T
  • Journal Title: Leukemia Volume: 26 Pages: 2483-2493
  • Peer Reviewed
• [Journal Article] Poly-ADP ribosylation of Miki by tankyrase-1 promotes centrosome maturation (2012)
  • Author(s): Ozaki Y, Matsui H, Asou H, Nagamachi A, Aki D, Honda H, Yasunaga S, Takihara Y, Yamamoto T, Izumi S, Ohsugi M, Inaba T
  • Journal Title: Mol Cell Volume: 47 Pages: 694-706
  • Peer Reviewed
• [Journal Article] Mouse Samd9l is not a functional paralogue of the human SAMD9, the gene mutated in normophosphataemic familial tumoral calcinosis (2012)
  • Author(s): Li Q, Guo H, Matsui H, Honda H, Inaba T, Sundberg JP, Sprecher E, Uitto J
  • Journal Title: Exp Dermatol Volume: 21 Pages: 554-556
  • Peer Reviewed
• [Journal Article] Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor (2012)
  • Author(s): Sugihara E, Shimizu T, Kojima K, Ohishi N, Kai K, Ishizawa J, Nagata K, Hashimoto N, Honda H, Kanno M, Miwa M, Okada S, Andreeff M, Saya H
  • Journal Title: Oncogene Volume: 31 Pages: 2849-2861
  • Peer Reviewed
• [Journal Article] Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor (2012)
  • Author(s): Sugihara E, Shimizu T, Kojima K, Ohishi N, Kai K, Ishizawa J, Nagata K, Hashimoto Nz, Kanno M, Miwa M, Okada S, Andreeff M, Saya H
  • Journal Title: Oncogene Volume: (In press)
  • Peer Reviewed
• [Journal Article] Cas-L regulates myeloid cell motility and suppresses progression of leukemia induced by p210Bcr/Abl (2011)
  • Author(s): Seo S, Nakamoto T, Takeshita M, Lu J, Sato T, Suzuki T, Kamikubo Y, Ichikawa M, Noda M, Ogawa S, Honda H, Oda H, Kurokawa M
  • Journal Title: Cancer Sci Volume: 102 Pages: 2109-2117
  • Peer Reviewed
• [Journal Article] The Samd9L gene : transcriptional regulation and tissue-specific expression in mouse development (2011)
  • Author(s): Jiang Q, Quaynor B, Sun A, Li Q, Matsui H, Honda H, Inaba T, Sprecher E, Uitto J
  • Journal Title: J Invest Dermatol Volume: 131 Pages: 1428-1434
  • Peer Reviewed
• [Journal Article] Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation (2011)
  • Author(s): Honda H, Takubo K, Oda H, Kosaki K, Tazaki T, Yamasaki N, Miyazaki K, Moore KA, Honda Zi, Suda T, Lemischka IR
  • Journal Title: Proc Natl Acad Sci USA Volume: 108 Pages: 2468-2473
  • Peer Reviewed
• [Presentation] Role of disease-related EED Ile363Met mutant in embryonic development and tumorigenesis (2014)
  • Author(s): Takeshi Ueda, Masashi Sanada, Hirotaka Matsui, Norimasa Yamasaki, Zen-ichiro Honda, Lee-Yung Shih, Hiraku Mori, Toshiya Inaba, Seishi Ogawa, and Hiroaki Honda
  • Organizer: 日本血液学会
  • Place of Presentation: ロイトン札幌
• [Presentation] ヒストン脱メチル化酵素Fbxl10の脱制御による白血病発症機構の解析 (2013)
  • Author(s): 本田浩章
  • Organizer: 新学術領域がん支援冬期シンポジウム
  • Place of Presentation: 東京
• [Presentation] MDSで同定されたポリコローム複合体構成因子EEDの機能欠失型変異体の解析 (2012)
  • Author(s): 上田健, 真田晶, 松井啓隆, 山崎憲政, 本田善一郎, 森啓, LEE-YUNG SHIH 稲葉俊哉, 小川誠司, 本田浩章
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都
  • Year and Date: 2012-10-19
• [Presentation] Analysis of leukemogenic mechanisms induced by deregulation of a histone demethylase, Fbx110 (2011)
  • Author(s): 本田浩章
  • Organizer: 日本分子生物学会
  • Place of Presentation: 横浜(招待講演)
  • Year and Date: 2011-12-14
• [Presentation] 骨髄異形成症候群におけるポリコローム複合体PRC構成因子EDDの機構欠失型変異 (2011)
  • Author(s): 上田健, 真田晶, 松井啓隆, 山崎憲政, 本田善一郎, 森啓, LEE-YUNG SHIH, 稲葉俊哉, 小川誠司, 本田浩章
  • Organizer: 第73回日本血液学会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-15
• [Presentation] Different mechanisms through which Samd9L, a-7/7q-responsible gene, contributes to leukemogenesis (2011)
  • Author(s): 長町安希子、松井啓隆、尾崎佑子、山崎憲政、小田秀明、稲葉俊哉、本田浩章
  • Organizer: 日本血液学
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-15
• [Presentation] -7/7q-責任遺伝子候補 Samd9L (2011)
  • Author(s): 長町安希子, 松井啓隆, 尾崎裕子, 山崎憲政, 小田秀明 , 稲葉俊哉 , 本田浩章
  • Organizer: 第73回日本血液学会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-14
• [Presentation] Eed mutations impairing polycomb repressive complex 2 function in myelodysplastic syndrome (2011)
  • Author(s): 上田健、真田昌、松井啓隆、山崎憲政、本田善一郎、Lee-Yung Shih、森啓、稲葉俊哉、小川誠司、本田浩章
  • Organizer: 日本血液学
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-14
• [Remarks]
  • URL: http://home.hiroshima-u.ac.jp/sosai/top.html
• [Remarks] 広島大学原爆放射線医科学研究所・疾患モデル解析研究分野
  • URL: http://home.hiroshima-u.ac.jp/sosai/top.html
• [Remarks]
  • URL: http://home.hiroshima-u.ac.jp/sosai/top.html