骨髄異形成症候群の造血抑制における、細胞競合の役割の解明

• Project Area: Cell competition: a mechanism for survival of the fittest in the multi-cellular community
• Project/Area Number: 15H01481
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: 黒川 峰夫 東京大学, 医学部附属病院, 教授 (80312320)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000); Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2015: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: 細胞競合 / 骨髄異形成症候群

Outline of Annual Research Achievements

骨髄異形成症候群(MDS)は多様な病態を含む不均一な疾患群だが、主に造血不全が問題となる病態である低risk MDSについては、その機序はこれまでのモデルだけでは十分に説明できず、MDS細胞との相互作用による正常造血幹細胞の抑制などの未知の機序の存在が示唆される。
我々は一般的な骨髄異形成症候群(MDS)のモデルであるNUP98-HOXD13(NHD13)トランスジェニックマウスから採取した造血細胞を正常造血細胞と混合し、致死量の放射線を照射したレシピエントマウスに移植してキメラマウスを作製した。白血球表面のCD45多型を利用したLy5.1/5.2システムを用いて、MDS発症過程における正常造血細胞の分化、増殖を解析した。生着後MDS発症前の段階において、コントロール群と比較し正常造血細胞の成熟顆粒球への分化が阻害されることを明らかにした。
またIn vitroの系において、NHD13をレトロウイルスを用いてマウス造血細胞に感染させ不死化した細胞を、骨髄造血ニッチを模したOP9細胞上で正常造血細胞と共培養したところ、キメラマウスの系と同様に正常造血細胞の成熟顆粒球への分化が抑制された。また、トランスウェルを用いてNHD細胞と正常造血細胞の直接接触を防いだ状態で共培養した系や、共培養後の培養上清を用いて正常造血細胞を培養した系では、正常造血の分化抑制は認めなかった。
これらの結果より、MDS細胞との直接接触により正常細胞の分化抑制が惹起され、MDSにおける造血抑制に関与している可能性が示唆された。
また、MDS細胞と共移植したキメラマウスの正常細胞中の骨髄球系前駆細胞をソートし、DNAマイクロアレイを用いて発現変動遺伝子を抽出した。今後遺伝学的解析によりその下流のシグナルを明らかにするとともに、当該分子の作用を阻害することで正常細胞の分化抑制が解除されるか検討する。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Cytoprotective autophagy maintains leukemia-initiating cells in murine myeloid leukemia. (2016)
  • Author(s): Sumitomo Y, Koya J, Nakazaki K, Kataoka K, Tsuruta-Kishino T, Morita K, Sato T, Kurokawa M.
  • Journal Title: Blood Volume: 128 Issue: 12 Pages: 1614-24
  • DOI: 10.1182/blood-2015-12-684696
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Adiponectin enhances antibacterial activity of hematopoietic cells by suppressing bone marrow inflammation. (2016)
  • Author(s): Masamoto Y, Arai S, Sato T, Yoshimi A, Kubota N, Takamoto I, Iwakura Y, Yoshimura A, Kadowaki T, Kurokawa M
  • Journal Title: Immunity Volume: 44 Issue: 6 Pages: 1422-33
  • DOI: 10.1016/j.immuni.2016.05.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] DNMT3A R882 mutants interact with polycomb proteins to block haematopoietic stem and leukaemic cell differentiation. (2016)
  • Author(s): Koya J, Kataoka K, Sato T, Bando M, Kato Y, Tsuruta-Kishino T, Kobayashi H, Narukawa K, Miyoshi H, Shirahige K, Kurokawa M.
  • Journal Title: Nat Commun. Volume: 7 Issue: 1 Pages: 10924-10924
  • DOI: 10.1038/ncomms10924
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] miR-133 regulates Evi1 expression in AML cells as a potential therapeutic target. (2016)
  • Author(s): Yamamoto H, Lu J, Oba S, Kawamata T, Yoshimi A, Kurosaki N, Yokoyama K, Matsushita H, Kurokawa M, Tojo A, Ando K, Morishita K, Katagiri K, Kotani A
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 10294-10294
  • DOI: 10.1038/srep19204
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Genetic basis of myeloid transformation in familial platelet disorder/acute myeloid leukemia patients with haploinsufficient RUNX1 allele (2016)
  • Author(s): Sakurai M, Kasahara H, Yoshida K, Yoshimi A, Kunimoto H, Watanabe N, Shiraishi Y, Chiba K, Tanaka H, Harada Y, Harada H, Kawakita T, Kurokawa M, Miyano S, Takahashi S, Ogawa S, Okamoto S, Nakajima H
  • Journal Title: Blood Cancer J Volume: 6 Issue: 2 Pages: e392-e392
  • DOI: 10.1038/bcj.2015.81
  • Peer Reviewed / Open Access
• [Journal Article] Adiponectin regulates psoriasiform skin inflammation by suppressing IL-17 production from γδ-T cells (2015)
  • Author(s): Shibata S, Tada Y, Hau C, Mitsui A, Kamata M, Asano Y, Sugaya M, Kadono T, Masamoto Y, Kurokawa M, Yamauchi T, Kubota N, Kadowaki T, and Sato S.
  • Journal Title: Nature communications Volume: 6 Issue: 1 Pages: 1-14
  • DOI: 10.1038/ncomms8687
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. (2015)
  • Author(s): Morita K, Masamoto Y, Kataoka K, Koya J, Kagoya Y, Yashiroda H, Sato T, Murata S, and Kurokawa M.
  • Journal Title: Leukemia Volume: 29 Issue: 11 Pages: 2248-56
  • DOI: 10.1038/leu.2015.137
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Targeted gene correction of RUNX1 in induced pluripotent stem cells derived from familial platelet disorder with propensity to myeloid malignancy restores normal megakaryopoiesis. (2015)
  • Author(s): 2.Iizuka H, Kagoya Y, Kataoka K, Yoshimi A, Miyauchi M, Taoka K, Kumano K, Yamamoto T, Hotta A, Arai S, Kurokawa M.
  • Journal Title: Exp Hematol. Volume: 43 Issue: 10 Pages: 849-857
  • DOI: 10.1016/j.exphem.2015.05.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Posttranslational modifications of RUNX1 as potential anticancer targets. (2015)
  • Author(s): Goyama S, Huang G, Kurokawa M, and Mulloy JC.
  • Journal Title: Oncogene Volume: 34 Issue: 27 Pages: 3483-92
  • DOI: 10.1038/onc.2014.305
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Patient-Derived Induced Pluripotent Stem Cells Identified SLITRK4 As a Causative Gene of Chronic Myelomonocytic Leukemia (2016)
  • Author(s): Sho Yamazaki, Kazuki Taoka, Shunya Arai, Masashi Miyauchi, Keisuke Kataoka, Akihide Yoshimi and Mineo Kurokawa
  • Organizer: 58th ASH Annual Meeting and Exposition
  • Place of Presentation: San Diego
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Identification of somatic mutation contributing to chemotherapy resistance in acute myeloid leukemia (2016)
  • Author(s): Akira Honda, Junji Koya, Akihide Yoshimi, Keisuke Kataoka, Shunya Arai, Mineo Kurokawa
  • Organizer: 58th ASH Annual Meeting and Exposition
  • Place of Presentation: San Diego
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Patient-Derived Induced Pluripotent Stem Cells Revealed ADAM8/CD156 as a Novel Marker of TKI-Resistant Chronic Myeloid Leukemia Cells (2016)
  • Author(s): Masashi Miyauchi, Shunya Arai, Akira Honda, Sho Yamazaki, Keisuke Kataoka, Akihide Yoshimi, Kazuki Taoka, Keiki Kumano, and Mineo Kurokawa
  • Organizer: 58th ASH Annual Meeting and Exposition
  • Place of Presentation: San Diego
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Single-Cell Gene Expression Analysis Identifieds Alcam As a Novel Candidate Therapeutic Target in AML (2016)
  • Author(s): Arika Shimura-Nukina, Yosuke Masamoto, Yuki Kagoya, Shunya Arai, Mineo Kurokawa
  • Organizer: 58th ASH Annual Meeting and Exposition
  • Place of Presentation: San Diego
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] 骨髄異形性症候群におけるアザシチジン治療抵抗性をもたらす遺伝子変異の網羅的解析 (2016)
  • Author(s): 塚本彩人、正本庸介、土井晃一郎、荒井俊也、森下真一、黒川峰夫
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Adipocyte-derived Adiponectin Regulates Hematopoietic Stem Cell Activation after Myelotoxic Injury (2016)
  • Author(s): 正本庸介、荒井俊也、佐藤智彦、高本偉碩、窪田直人、門脇孝、黒川峰夫
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Pre-HPCs derived from CML-iPSCs represent a platform for analysis of TKI-resistant CML stem cells (2016)
  • Author(s): Masashi Miyauchi, Shunya Arai, Akira Honda, Sho Yamazaki, Keisuke Kataoka, Akihide Yoshimi, Kazuki Taoka, Keiki Kumano, and Mineo Kurokawa
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Single-cell gene expression analysis reveals a novel candidate AML stem cell-specific antigen, ALCAM (2016)
  • Author(s): Arika Shimura-Nukina, Yosuke Masamoto, Yuki Kagoya, Shunya Arai, Mineo Kurokawa
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Investigation of causative genes in CMML through patient-derived induced pluripotent stem cells (2016)
  • Author(s): Sho Yamazaki, Kazuki Taoka, Shunya Arai, Masashi Miyauchi, Keisuke Kataoka, Akihide Yoshimi, and Mineo Kurokawa
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Heterozygous Dnmt3a mutation induces expansion of hematopoietic stem cell pool in a murine model (2016)
  • Author(s): Takashi Higo, Junji Koya, Yoshiki Sumitomo, Takako Tsuruta-Kishino, Keisuke Kataoka, Tomohiko Sato, and Mineo Kurokawa
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Pre-HPCs derived from CML-iPSCs, as a platform of CML stem cells, reveal a novel marker of TKI-resistant CML cells. (2016)
  • Author(s): Masashi Miyauchi, Shunya Arai, Akira Honda, Sho Yamazaki, Keisuke Kataoka, Akihide Yoshimi, Kazuki Taoka, Keiki Kumano, and Mineo Kurokawa
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Investigation of causative genes in CMML through patient-derived induced pluripotent stem cells (2016)
  • Author(s): Sho Yamazaki, Kazuki Taoka, Shunya Arai, Masashi Miyauchi, Keisuke Kataoka, Akihide Yoshimi, and Mineo Kurokawa
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Identification of somatic mutation contributing to chemotherapy resistance in acute myeloid leukemia (2016)
  • Author(s): Akira Honda, Junji Koya, Akihide Yoshimi, Keisuke Kataoka, Sｈunya Arai, Mineo Kurokawa
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] 白血病幹細胞に特異的な表面抗原の探索 (2016)
  • Author(s): 志村（貫名）有香、籠谷勇紀、荒井俊也、黒川峰夫
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Pre-hematopoietic progenitor cells (CD34+CD43+CD45-) form CML-iPSCs as powerful platform for analysis of TKI-resistant CML stem cells. (2016)
  • Author(s): Masashi Miyauchi, Shunya Arai, Akira Honda, Sho Yamazaki, Kensuke Kataoka, Akihide Yoshimi, Kazuki Taoka, Keiki Kumano and Mineo Kurokawa
  • Organizer: International Society of Stem Cell Research (ISSCR) 2016 annual meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] Adipocyte-derived adiponectin regulates hematopoietic stem cell activation through mTORC1 potentiation after myelotoxic Injury (2016)
  • Author(s): Yosuke Masamoto, Shunya Arai, Tomohiko Sato, Iseki Takamoto, Naoto Kubota, Takashi Kadowaki, and Mineo Kurokawa
  • Organizer: International Society of Stem Cell Research (ISSCR) 2016 annual meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] 白血病幹細胞に特異的な表面抗原の探索 (2016)
  • Author(s): 志村 有香、黒川 峰夫
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府
  • Year and Date: 2016-05-31
• [Presentation] Adipocyte-derived adiponectin positively regulates exit from quiescence of hematopoietic stem cells by potentiating mTORC1 activation after myelotoxic Injury. (2015)
  • Author(s): Yosuke Masamoto, Shunya Arai, Tomohiko Sato, Iseki Takamoto, Naoto Kubota, Takashi Kadowaki and Mineo Kurokawa
  • Organizer: 57th ASH Annual Meeting and Exposition
  • Place of Presentation: Orland(USA)
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] Heterozygous Dnmt3a mutation induces expansion of hematopoietic stem cell pool in a murine model (2015)
  • Author(s): Takashi Higo, Junji Koya, Yoshiki Sumitomo, Takako Tsuruta-Kishino, Keisuke Kataoka, Tomohiko Sato and Mineo Kurokawa
  • Organizer: 57th ASH Annual Meeting and Exposition
  • Place of Presentation: Orland(USA)
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] Autophagy promote murine myeloid leukemia progression and potentiate effect of cytarabine in vivo (2015)
  • Author(s): Yoshiki Sumitomo, Junji Koya, Keisuke Kataoka, Takako Tsuruta-Kishino, Ken Morita, Tomohiko Sato, Mineo Kurokawa
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: ホテル日航金沢(石川県金沢市)
  • Year and Date: 2015-10-16
• [Presentation] オートファジー関連遺伝子の欠損はマウス骨髄性白血病の進展を阻害しシタラビン感受性を高める. (2015)
  • Author(s): Yoshiki Sumitomo, Junji Koya, Keisuke Kataoka, Ken Morita, Tomohiko Sato, Mineo Kurokawa.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県名古屋市)
  • Year and Date: 2015-10-08
• [Remarks] 東京大学医学部附属病院 血液・腫瘍内科
  • URL: http://www.u-tokyo-hemat.com/
• [Remarks] 東京大学医学部附属病院血液/腫瘍内科
  • URL: http://www.u-tokyo-hemat.com