Molecular pathogenesis of abnormal kpm (Lats2) expression in leukemia

• Project/Area Number: 20591122
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Ritsumeikan University
• Principal Investigator: HORI Toshiyuki Ritsumeikan University, 生命科学部, 教授 (70243102)
• Co-Investigator(Renkei-kenkyūsha): KAWAMATA Shin 先端医療振興財団, 先端医療センター研究所, 専門役 (00360842)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2009: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2008: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 癌 / 白血病 / シグナル伝達 / Hippo経路 / kpm(Lats2) / 薬剤耐性 / RASSF / 薬剤反応性

Research Abstract

Kpm (Lats2) is a serine-threonine kinase that is one of the core components of the Hippo signaling pathway. We measured expression levels of kpm (Lats2) in various leukemias and found that expression of kpm was downregulated in refractory leukemias. Knockdown of kpm (Lats2) rendered leukemic cells resistant to anti-cancer drugs. We demonstrated that stabilization of nuclear p73 after DNA damage and subsequent induction of PUMA and p21 require phosphorylation of YAP2 at serine-127 by Kpm (Lats2). Thus, downregulation of kpm (Lats2) seems to be one of the mechanisms for chemoresistance.

Research Products

• [Journal Article] TSLP fosters human breast cancer tumor development by promoting type 2 inflammation. (2011)
  • Author(s): Alexander Pedroza-Gonzalez1, Kangling Xu, Te-Chia Wu, Caroline Aspord, Sasha Tindle, Florentina Marches, Michael Gallegos, Elizabeth C. Burton, Daniel Savino, Toshiyuki Hori, Yuetsu Tanaka, Sandra Zurawski, Gerard Zurawski, Laura Bover, Yong-Jun Liu, Jacques, Banchereau, A.Karolina Palucka
  • Journal Title: J.Exp.Med. 208 Pages: 479-490
  • Peer Reviewed
• [Journal Article] TSLP fosters human breast cancer tumor development by promoting type 2 inflammation. (2011)
  • Author(s): A.Pedroza-Gonzalez, et al.
  • Journal Title: J.Exp.Med. Volume: 208 Pages: 479-490
  • Peer Reviewed
• [Journal Article] The CD70-CD27 interaction during the stimulation withdendritic cells promotes naive CD4^+ T cells to develop into T cells producing a broad array of immunostimulatory cytokines in humans. (2009)
  • Author(s): Mutsumi Hashimoto, Toshio Kitawaki, Norimitsu Kadowaki, Satoshi Iwata, Chikao Morimoto, Toshiyuki Hori, Takashi Uchiyama
  • Journal Title: Int.Immunol. 21 Pages: 891-904
  • NAID: 10025387511
  • Peer Reviewed
• [Journal Article] Human plasmacytoid dendritic cells express an atrial natriuretic peptide receptor, guanylyl cyclase-A. (2009)
  • Author(s): Rimpei Morita, Tomoko Fujita, Takashi Uchiyama, Toshiyuki Hori
  • Journal Title: Microbiol.Immunol. 53 Pages: 403-411
  • NAID: 10027686984
  • Peer Reviewed
• [Journal Article] Mycophenolate mofetil combined with tacrolimus and minidose methotrexate after unrelated donor bone marrow transplantation with reduced-intensity conditioning. (2009)
  • Author(s): Chisaki Mizumoto, Junya Kanda, Tatsuo Ichinohe, Takayuki Ishikawa, Masashi Matsui, Norimitsu Kadowaki, Tadakazu Kondo, Kazunori, Imada, Masakatsu Hishizawa, Hiroshi Kawabata, Momoko Nishikori, Kouhei Yamashita, Akifumi Takaori-Kondo, Toshiyuki Hori, Takashi Uchiyama
  • Journal Title: Int.J.Hematol. 89 Pages: 538-545
  • NAID: 10025161531
  • Peer Reviewed
• [Journal Article] Human plasmacytoid dendritic cells express an atrial natriuretic peptide receptor, guanylyl cyclase-A. (2009)
  • Author(s): R.Morita, et al.
  • Journal Title: Microbiol.Immunol. 53 Pages: 403-411
  • Peer Reviewed
• [Journal Article] The CD70-CD27 interaction during the stimulation withdendritic cells promotes naive CD4+T cells to develop into Tcells producing a broad array of immunostimulatory cytokines in humans. (2009)
  • Author(s): Mutsumi Hashimoto, et al.
  • Journal Title: Int.Immunol. 21 Pages: 891-904
  • Peer Reviewed
• [Journal Article] Kpm/Lats2 is linked to chemosensitivity of leukemic cellsthrough the stabilization of p73. (2008)
  • Author(s): Masahiro Kawahara, Toshiyuki Hori, Tsutomu Oka, Marius Sudol, Takashi Uchiyama
  • Journal Title: Blood 112 Pages: 3856-3866
  • Peer Reviewed
• [Journal Article] Growth and differentiation advantages of CD4^+ OX406+ T cells from allogeneic hematopoietic stem cell transplantation recipients. (2008)
  • Author(s): Takero Shindo, Takakyuki Ishikawa, Akiko Fukunaga, Toshiyuki Hori, Takashi Uchiyama
  • Journal Title: Biol.Blood Marrow Tr. 14 Pages: 268-281
  • Peer Reviewed
• [Journal Article] Kpm/Lats2 is linked to chemo-sensitivity of leukemic cells through the stabilization of p73 (2008)
  • Author(s): T. Kawahara, T. Hori, et al.
  • Journal Title: Blood 112 Pages: 3856-3866
  • Peer Reviewed
• [Journal Article] Growth and differentiation advantages of CD4+OX40+T cells from allogeneic hematopoietic stem cell transplantation recipients (2008)
  • Author(s): T. Shindo, T. Ishikawa, A. Fukunaga, T. Hori, et al.
  • Journal Title: Biol. Blood Marrow Transplant. 14 Pages: 268-281
  • Peer Reviewed
• [Presentation] C.elegansにおけるRASSF相同体T24F1.3の機能解析 (2010)
  • Author(s): 竹中元彦、井上英樹、香座知典、堀利行
  • Organizer: 第33回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド(兵庫県)
  • Year and Date: 2010-12-10
• [Presentation] WartsのC.elegans相同体Wts-1と相互作用する細胞分子の探索 (2010)
  • Author(s): 香座知典、井上英樹、竹中元彦、堀利行
  • Organizer: 第33回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド(兵庫県)
  • Year and Date: 2010-12-10
• [Presentation] WartsのC.elegans相同体Wts-1と相互作用する細胞分子の探索 (2010)
  • Author(s): 香座知典, 他3名
  • Organizer: 第33回日本分子生物学会
  • Place of Presentation: 神戸ポートアイランド(兵庫県)
  • Year and Date: 2010-12-10
• [Presentation] C.elegansにおけるRASSF相同体T24F1.3の機能解析 (2010)
  • Author(s): 竹中元彦, 他3名
  • Organizer: 第33回日本分子生物学会
  • Place of Presentation: 神戸ポートアイランド(兵庫県)
  • Year and Date: 2010-12-10
• [Presentation] Poor tolerability to imatinib in elderly CML patients may lead to inadequate responses. (2010)
  • Author(s): Masatoshi Nishikawa, Tadakazu Kondo, Masakatsu Hishizawa, Momoko Nishikori, Kohei Yamashita, Toshiyuki Kitano, Tatsuo Ichinohe, Hiroshi Kawabata, Akifumi Takaori, Norimitsu Kadowaki, Toshiyuki Hori, Hiroshi Takayama, Takayuki Ishikawa, Takashi Uchiyama
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-26
• [Presentation] Autologous stem cell transplantation for 32 patients with multiple myeloma. (2010)
  • Author(s): Wataru Kishimoto, Tadakazu Kondo, Kouhei Yamashita, Hiroshi Kawabata, Tatsuo Ichinohe, Akifumi Takaori, Norimitsu Kadowaki, Toshiyuki Hori, Takayuki Ishikawa, Takashi Uchiyama
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-25
• [Presentation] Kpm/Lats2 of the Hippo pathway is linked to chemo-sensitivity of leukemic cells. (2008)
  • Author(s): Masahiro Kawahara, Toshiyuki Hori, Kazuhisa Chonabayashi, Tsutomu Oka, Marius Sudol, Takashi Uchiyama
  • Organizer: The 50th Annual Meeting of American Society of Hematology
  • Place of Presentation: San Francisco (Poster session)
  • Year and Date: 2008-12-06
• [Presentation] Relationship between the Hippo pathway and DNA damage signals : Kpm/Lats2 affects chemo-sensitivity of leukemic cells. (2008)
  • Author(s): Masahiro Kawahara, Kazuhisa Chonabayashi, Takashi Uchiyama, Tsutomu Oka, Marius Sudol, Toshiyuki Hori
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知)
  • Year and Date: 2008-10-28
• [Presentation] 非血縁者間同種骨髄移植後の非感染性肺合併症:緩和な前処置と従来型前処置の比較 (2008)
  • Author(s): 篠原正信、諌田淳也、一戸辰夫、丸山亙、山本和代、石上隆宏、内山達樹、阪本貴士、藤田晴之、小林正行、錦織桃子、菱澤方勝、川端浩、門脇則光、高折晃史、堀利行、山下浩平、近藤忠一、石川隆之、内山卓
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都国際会館(京都府)(一般口演)
  • Year and Date: 2008-10-12
• [Presentation] 単一施設における複数回同種移植に関する検討 (2008)
  • Author(s): 丸山亙、一戸辰夫、山本和代、石上隆宏、内山達樹、篠原正信、阪本貴士、藤田晴之、菱澤方勝、錦織桃子、山下浩平、近藤忠一、川端浩、高折晃史、門脇則光、堀利行、石川隆之、内山卓
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都国際会館(京都府)(一般口演)
  • Year and Date: 2008-10-11
• [Presentation] 穏和な前処置を用いた同種造血幹細胞移植後の造血器腫瘍再発例の予後に関する検討 (2008)
  • Author(s): 内山達樹、一戸辰夫、丸山亙、山本和代、石上隆宏、篠原正信、阪本貴士、藤田晴之、小林正行、錦織桃子、菱澤方勝、川端浩、門脇則光、高折晃史、堀利行、山下浩平、近藤忠一、石川隆之、内山卓
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都国際会館(京都府)(一般口演)
  • Year and Date: 2008-10-11
• [Presentation] 難治性白血病におけるHippo経路の破綻と治療抵抗性の分子機構 (2008)
  • Author(s): 堀利行、河原真大、蝶名林和久、内山卓
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都国際会館(京都府)(一般口演)
  • Year and Date: 2008-10-11
• [Presentation] 臍帯血移植後にdonor cell leukemiaを発症した悪性リンパ腫の1例 (2008)
  • Author(s): 山本和代、近藤忠一、菱澤方勝、錦織桃子、山下浩平、一戸辰夫、川端浩、高折晃史、門脇則光、堀利行、石川隆之、内山卓
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都国際会館(京都府)(一般口演)
  • Year and Date: 2008-10-10
• [Presentation] Kpm/Lats2 of the Hippo Pathway Is Linked to Chemo-Sensltivity of Leukemic Cells (2008)
  • Author(s): M. Kawahara, T. Hori, et al.
  • Organizer: 50^<th> Annual Meeting of American Society of Hematology
  • Place of Presentation: サンフランシスコ(アメリカ合衆国)
• [Presentation] 難治性白血病におけるHippo経路の破綻と治療抵抗性の分子機構 (2008)
  • Author(s): 堀利行, 河原真大, 他2名
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都国際会館(京都府)
• [Presentation] Relationship between the Hippo pathway and DNA damage signals : Kpm/Lats2 affects chemo-sensitivity of leukemic cells (2008)
  • Author(s): M. Kawahara, T. Hori, et al.
  • Organizer: 第67回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場(愛知県)
• [Remarks] ホームページ等
  • URL: http://www.ritsumei.ac.jp/lifescience/bm/hori/lab.html