The Role Of Osteoclasts In the developing Leukemic Stem Cell Niche in a Mouse Model of Adult T-Cell Leukemia

• Project/Area Number: 25461440
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Mizukami Takuo 国立感染症研究所, 血液・安全性研究部, 室長 (60415487)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 癌幹細胞 / ニッチ / 微小環境 / 破骨細胞 / 骨浸潤抑制 / Zoledronic acid / HTLV-1 / ATL / Tax Transgenic mouse / Niche / ATL stem cells / ATL癌幹細胞 / HTLV / 成人T細胞白血病 / カルシウム血症

Outline of Final Research Achievements

Adult T cell leukemia (ATL) is a lymphoproliferative disorder caused by infection with HTLV-I. Although various chemotherapies have shown significant complete remission rates, most of the treated patients relapse. These data indicate the existence of leukemic stem cells (LSCs) and a specific niche that protects from chemotherapies. We identified that ATL-LSCs have reproduced the original tumor. Using homing assay, we found that more than 60% of first colonized cells in the spleen and BM were AT-LSCs and ATL-LSCs were also attached to the reticular cells in the trabecular bone. We also found the number of osteoclast was significantly increased at the trabecular region. To clarify the role of osteoclast, we treated osteoclast inhibitor Zoledronic acid. As a result, ATL cells were dramatically reduced in the BM and extend the mouse survival rate significantly in this treatment. These data suggest osteoclast have a potential therapeutic target in the mouse model of ATL.

Research Products

• [Journal Article] Impact of the SCF signaling pathway on leukemia stem cell-mediated ATL initiation and progression in an HBZ transgenic mouse model. (2016)
  • Author(s): Kuribayashi W, Takizawa K, Sugata K, Kuramitsu M, Momose H, Sasaki E, Hiradate Y, Furuhata K, Asada Y, Iwama A, Matsuoka M, Mizukami T*, Hamaguchi I*.
  • Journal Title: Oncotarget Volume: 7(32) Issue: 32 Pages: 51027-51043
  • DOI: 10.18632/oncotarget.10210
  • Peer Reviewed / Open Access
• [Journal Article] Standardization of quantitative PCR for human T-cell leukemia virus type 1 in Japan: A collaborative study (2015)
  • Author(s): Kuramitsu M, Okuma K, Yamochi T. et al
  • Journal Title: J. Clin. Microbien. Volume: 53 Issue: 11 Pages: 3485-3491
  • DOI: 10.1128/jcm.01628-15
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Establishment of a new quality control and vaccine safety test for influenza vaccines and adjuvants using gene expression profiling. (2015)
  • Author(s): Momose H, Mizukami T, Kuramitsu M, Takizawa K, Masumi A, Araki K, Furuhata K, Yamaguchi K, Hamaguchi I.
  • Journal Title: PLoS One Volume: 10 Issue: 4 Pages: e0124392-e0124392
  • DOI: 10.1371/journal.pone.0124392
  • Peer Reviewed
• [Journal Article] Identification of TL-Om1, an ATL Cell Line, as a Reference Material for Human T-Lymphotropic Virus 1 Quantitative PCR. (2015)
  • Author(s): Kuramitsu M, Okuma K, Yamagishi M, Yamochi T, Firouzi S, Momose H, Mizukami T, Takizawa K, Araki K, Sugamura K, Yamaguchi K, Watanabe T, Hamaguchi I.
  • Journal Title: Journal of Clinical Microbiology Volume: 53 Issue: 2 Pages: 587-596
  • DOI: 10.1128/jcm.02254-14
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] B-cell-intrinsic hepatitis C virus expression leads to B-cell-lymphomagenesis and induction of NF-κB signalling (2014)
  • Author(s): Kasama Y, Mizukami T, Kusunoki H, Peveling-Oberhag J, Nishito Y, Ozawa M, Kohara M, Mizuochi T, Tsukiyama-Kohara K
  • Journal Title: PLoS One Volume: 9(3) Issue: 3 Pages: 91373-91373
  • DOI: 10.1371/journal.pone.0091373
  • Peer Reviewed / Open Access
• [Journal Article] Degenerate polymerase chain reaction strategy with DNA microarray for detection of multiple and various subtypes of virus during blood screening (2013)
  • Author(s): Takizawa K, Nakashima T, Mizukami T, Kuramitsu M, Endoh D, Kawauchi S, Sasaki K, Momose H, Kiba Y, Mizutani T, Furuta RA, Yamaguchi K, Hamaguchi I
  • Journal Title: Transfusion. Volume: 17 Issue: 10pt2 Pages: 17-17
  • DOI: 10.1111/trf.12193
  • Peer Reviewed
• [Presentation] 成人T細胞白血病 (ATL) モデルマウスにおけるATL癌幹細胞の発生維持機構におけるc-kit-SCFシグナルの重要性の解明. (2016)
  • Author(s): 水上拓郎, 栗林和華子, 滝澤和也, 倉光球, 佐々木永太, 平舘裕希, 浅田善久, 岩間厚志, 松岡雄雅, 濵口功.
  • Organizer: 第159回 日本獣医学会
  • Place of Presentation: 日本大学生物資源科学部
  • Year and Date: 2016-09-06
• [Presentation] ※ ○ The essential role of c-kit-SCF signaling in the leukemic stem cells mediated ATL cell propagation and drug resistance. (2016)
  • Author(s): Kuribayashi W, Mizukami T, Takizawa K, Sugata K, Kuramitsu M, Nojima K, Momose H, Iwama A, Matsuoka M, Hamaguchi I.
  • Organizer: The 5th JCA-AACR Special Joint Conference
  • Place of Presentation: Tokyo Bay Maihama Hotel
  • Year and Date: 2016-07-13
• [Presentation] The c-kit-SCF signaling in the leukemic stem cells development and differentiation in ATL model mice. (2016)
  • Author(s): Kuribayashi W, Mizukami T, Takizawa K, Sugata K, Kuramitsu M, Nojima K, Momose H, Iwama A, Matsuoka M, Hamaguchi I
  • Organizer: RIKEN IMS Summer Program (RISP) 2016
  • Place of Presentation: 理化学研究所
  • Year and Date: 2016-06-10
• [Presentation] The c-kit-SCF signaling in the leukemic stem cells development and differentiation in ATL model mice. (2015)
  • Author(s): Wakako Kuribayashi, Takuo Mizukami, Kazuya Takizawa, Kenji Sugata, Madoka Kuramitsu, Kiyoko Nozima, Haruka Momose, Yoshihisa Asada, Atsushi Iwama, Masao Matsuoka, Isao Hamaguchi.
  • Organizer: 第77回日本血液学会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] The c-kit-SCF signaling in the leukemic stem cells development in ATL model mice (2015)
  • Author(s): Wakako Kuribayashi, Takuo Mizukami, Masao Matsuoka, Isao Hamaguchi
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] Identification of ATL stem cells in an ATL model HBZ transgenic mouse (2015)
  • Author(s): Wakako Kuribayashi, Takuo Mizukami, Kazuya Takizawa, Kenji Sugata, Madoka Kuramitsu, Kiyoko Nojima, Haruka Momose, Yoshihisa Asada, Atsushi Iwama, Masao Matsuoka, Isao Hamaguchi
  • Organizer: International Society for Experimental Hematology
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2015-09-17
  • Int'l Joint Research
• [Presentation] HBZ-Tgマウスモデルにおける癌幹細胞の機能解析 (2015)
  • Author(s): 栗林和華子, 水上拓郎
  • Organizer: 第２回 HTLV-1学会
  • Place of Presentation: 東京大学医科学研究所
  • Year and Date: 2015-08-22
• [Presentation] IDENTIFICATION OF LEUKEMIC STEM CELL CANDIDATES IN AN ATL MOUSE MODEL OF HBZ TRANSGENIC MICE (2015)
  • Author(s): Wakako Kuribayashi, Takuo Mizukami, Kazuya Takizawa, Kenji Sugata, Madoka Kuramitsu, Kiyoko Nozima, Haruka Momose, Yoshihisa Asada, Astushi Iwama, Masao Matsuoka, Isao Hamaguchi,
  • Organizer: European hematology association
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2015-06-11
  • Int'l Joint Research
• [Presentation] ATLモデルマウスにおけるがん幹細胞のc-kit-SCFの機能解析 (2015)
  • Author(s): 栗林和華子, 水上拓郎
  • Organizer: Kyoto T Cell Conference
  • Place of Presentation: 京都
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Presentation] Identification and characterization of cancer stem cells in an HBZ transgeni c mouse model of ATL (2014)
  • Author(s): Wakako Kuribayashi, Takuo Mizukami, Kazuya Takizawa, Madoka Kuramitsu, Iwama Atsushi, Yoshihisa Asada, Masao Matsuoka, Isao Hamaguchi
  • Organizer: 日本血液学会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] 造血組織における新たな一過性ニッチ細胞 (TNCs)の同定とその多様な機能 (2014)
  • Author(s): 水上拓郎、滝澤和也、平松竜司、倉光球、百瀬暖佳、山口一成、浜口功
  • Organizer: 日本獣医学会
  • Place of Presentation: 北海道大学高等教育推進機構
  • Year and Date: 2014-09-09 – 2014-09-12
• [Presentation] HTLV-1モデルマウスであるHBZ-Tgマウスにおける癌幹細胞の同定と機能解析 (2014)
  • Author(s): 栗林和華子, 水上拓郎, 滝澤和也, 倉光球, 浅田善久, 岩間厚志, 松岡雅雄, 濵口功
  • Organizer: HTLV-1学会
  • Place of Presentation: 東京大学医科学研究所
  • Year and Date: 2014-08-16 – 2014-08-24
• [Presentation] 成人T細胞白血病 (ATL)モデルマウスであるHBZトランスジェニックマウスにおける癌幹細胞の同定の試み (2014)
  • Author(s): 栗林和華子, 水上拓郎, 滝澤和也, 倉光球, 浅田善久, 岩間厚志, 松岡雅雄, 濵口功
  • Organizer: 京都T細胞会議
  • Place of Presentation: 京都平安ホテル
  • Year and Date: 2014-05-16 – 2014-05-17
• [Presentation] The Role Of Osteoclasts In the developing Leukemic Stem Cell Niche in a Mouse Model of Adult T-Cell Leukemia (2013)
  • Author(s): Takuo Mizukami, Kazuya Takizawa, Madoka Kuramitsu, Haruka Momose, **Jumpei Yamazaki, ***William Hall, *Hideki Hasegawa, Kazunari Yamaguchi, Isao Hamaguchi
  • Organizer: 18回欧州血液学会
  • Place of Presentation: Sweden, Stockholm
• [Presentation] ATLマウスモデルであるHBZ-TgマウスにおけるATLがん幹細胞の同定 (2013)
  • Author(s): 栗林和華子1),2)、 水上拓郎2)、滝澤和也2)、倉光球2)、百瀬暖佳2)、 菅田謙治3)、浅田善久1)、松岡雅雄3)、濵口功2)
  • Organizer: HTLV-1研究会
  • Place of Presentation: 東京大学
  • Invited
• [Presentation] トランスジェニックマウスを用いた 「感染症と癌」のクロストーク (2013)
  • Author(s): 水上拓郎、滝澤和也、狭間俊介、倉光球、百瀬暖佳、益見厚子、長谷川秀樹、浜口功
  • Organizer: 日本獣医学会 サテライトフォーラム
  • Place of Presentation: 岐阜大学
• [Presentation] 成人T細胞白血病マウスモデルを用いた癌幹細胞ニッチ形成における破骨細胞の機能解析と破骨細胞を標的とした治療法の開発 (2013)
  • Author(s): 水上 拓郎 1,滝澤 和也 1,栗林 和華子 2,平松 竜司 1,倉光 球 1, 山崎 淳平 3,William Hall4,長谷川 秀樹 5,山口 一成 1,浜口 功 1
  • Organizer: 日本獣医学会
  • Place of Presentation: 岐阜大学
• [Presentation] The role of osteoclast in the leukemic stem cell niche using a mouse model of adult T cell leukemia (2013)
  • Author(s): Takuo Mizukami, Kazuya Takizawa, Wakako Kuribayashi, Ryuji Hiramatsu, Madoka Kuramitsu, Haruka Momose, Jumpei Yamazaki, William W Hall, Hideki Hasegawa, Kazunari Yamaguchi, Isao Hamaguchi
  • Organizer: 日本血液学会
  • Place of Presentation: 北海道
• [Presentation] The Osteoclast Targeting Therapy In Bone Metastasis For a Mouse Model Of Adult T Cell Leukemia (2013)
  • Author(s): Takuo Mizukami, PhD1*, Kazuya Takizawa, PhD1*, Jumpei Yamazaki, PhD2*, Wakako Kuribayashi3*, Madoka Kuramitsu, PhD1*, Ryuji Hiramatsu, PhD1*, William W Hall, MD, PhD4*, Hideki Hasegawa, MD, PhD5*, Kazunari Yamaguchi, MD, PhD1* and Isao Hamaguchi, MD, PhD1
  • Organizer: 55th Annual Meeting of American Society of Hematology
  • Place of Presentation: New Orleans