Establishment of xeno-transplantaion model for normal and malignant hematopoiesis using human niche.

• Project/Area Number: 20390276
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Tokai University
• Principal Investigator: ANDO Kiyoshi Tokai University, 医学部, 教授 (70176014)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥19,110,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥4,410,000); Fiscal Year 2010: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2009: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
• Keywords: ヒト造血ニッチ / 造血幹細胞 / 白血病幹細胞 / ニッチ / ヒト造血幹細胞 / NOGマウス / Jagged-1 / 多発性骨髄腫 / 老化 / 活性酸素 / ヒト造血幹細胞維持 / SDF-1 / N-cadherin / Angiopoietin-1

Research Abstract

We established xeno-transplantaion model using immune-deficient mice to analyze normal and pathological human hematopoiesis. First we demonstrated that replication stress induces intracellular elevation of reactive oxygen species (ROS) that results in accumulated and persistent DNA damage in human HSCs both in vitro and in vivo. The oxidative DNA damage causes premature senescence among HSCs, leading to loss of stem cell function. Importantly, treatment with an antioxidant can antagonize oxidative DNA damage and consequent HSC dysfunction. Our results reveal that ROS play a causative role for DNA damage, and mechanisms of ROS regulation have a major influence on human HSC aging. Then, to establish suitable in vivo MDS model, we intramedurally transplanted CD34^+ cells from the patients with MDS, acute myelogenous leukemia (AML) derived from MDS (MDS-AML), and AML with trilineage dysplasia into nonobese diabetic/Severe combined immunodeficient/IL-2Rγ^<null> (NOG) mice with co-injection of human mesenchymal stem cells. They were engrafted in bone marrow (BM) of NOG mice, although their efficiency was less than the normal CD34^+ BM cells. Histologically, CD34^+ cells derived from MDS patients were aligned along endosteus of BM, whereas the differentiated cells were located in the central medullary regions. The distribution was abrogated using CD34^+ BM cells from MDS-AML. These findings suggest that this in vivo MDS model is useful for elucidating the pathogenesis of MDS

Research Products

• [Journal Article] Establishment of xenograft model of human myelodysplastic syndromes (2011)
  • Author(s): Muguruma Y, Matsushita H, Yahata T, Yumino S, Tanaka Y, Miyachi H, Ogawa Y, Kawada H, Ito M, Ando K
  • Journal Title: Hematologica (in press)
• [Journal Article] Melphalan-Prednisone and Vincristine-Doxorubicin-Dexamethasone Chemotherapy Followed by Prednisone/Interferon Maintenance Therapy for Multiple Myeloma : Japan Clinical Oncology Group Study, JCOG0112 (2011)
  • Author(s): Chou T, Tobinai K, Uike N, Asakawa T, Saito I, Fukuda H, Mizoroki F, Ando K, Iida S, Ueda R, Tsukasaki K, Hotta T, other members of the Lymphoma Study Group (LSG) of Japan Clinical Oncology Group (JCOG), Japan
  • Journal Title: Jpn J Clin Oncol (in press)
• [Journal Article] Safety and Efficacy of the Terminal Complement Inhibitor Eculizumab in Japanese Patients with Paroxysmal Nocturnal Hemoglobinuria : The AEGIS Clinical Trial (2011)
  • Author(s): Kanakura Y, Ohyashiki K, Shichishima T, Okamoto S, Ando K, Ninomiya H, Kawaguchi T, Nakao S, Nakakuma H, Nishimura J, Kinoshita T, Bedrosian CL, Valentine ME, Khursigara G, Ozawa K, Omine M
  • Journal Title: Int J Hematol (in press)
  • NAID: 10029532438
• [Journal Article] Clinical efficacy and safety of biapenem for febrile neutropenia in patients with underlying hematopoietic diseases : a multi-institutional study (2011)
  • Author(s): Nakagawa Y, Suzuki K, Hirose T, Chou T, Fujisawa S, Kida M, Usuki K, Ishida Y, Taniguchi S, Kouzai Y, Tomoyasu S, Miyazaki K, Higashihara M, Ando K, Aoki S, Arai A, Akiyama N, Hatake K, Okamoto S, Dan K, Ohyashiki K, Urabe A
  • Journal Title: J Infect Chemother. (in press)
  • NAID: 10027816744
• [Journal Article] Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic stem cell transplant recipients (2011)
  • Author(s): Onizuka M, Kunii N, Toyosaki M, Machida S, Ohgiya D, Ogawa Y, Kawada H, Inoko H, Ando K
  • Journal Title: Bone Marrow Transplant (in press)
• [Journal Article] Melphalan-Prednisone and Vincristine-Doxorubicin-Dexamethasone Chemotherapy Followed by Prednisone/Interferon Maintenance Ther apy for Multiple Myeloma : Japan Clinical Oncology Group Study, JCOG0112 (2011)
  • Author(s): Chou, et al
  • Journal Title: J Infect Chemother Volume: (In press)
  • Peer Reviewed
• [Journal Article] Safety and Efficacy of the Terminal Complement Inhibitor Eculizumab in Japanese Patients with Paroxysmal Nocturnal Hemoglobinuria : The AEGIS Clinical Trial (2011)
  • Author(s): Kanakura, et al
  • Journal Title: Int J Hematol Volume: (In press)
  • Peer Reviewed
• [Journal Article] Clinical efficacy and safety of biapenem for febrile neutropenia in patients with underlying hematopoietic diseases : a multi-institutional study (2011)
  • Author(s): Nakagawa, et al
  • Journal Title: J Infect Chemother Volume: (In press)
  • Peer Reviewed
• [Journal Article] Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic stem cell transplant recipients (2011)
  • Author(s): Onizuka, et al
  • Journal Title: Bone Marrow Transplant Volume: (In press)
  • Peer Reviewed
• [Journal Article] Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells (2011)
  • Author(s): Yahata, et al
  • Journal Title: Blood Volume: (in press)
  • Peer Reviewed
• [Journal Article] Bendamustine Is Highly Effective for Relapsed or Refractory Indolent B-Cell Non-Hodgkin Lymphoma (B-NHL) and Mantle Cell Lymphoma (MCL) : Final Results of a Japanese Multicenter Phase II Study (2010)
  • Author(s): Ohmachi K, Ando K, Ogura M, Uchida T, Itoh K, Kubota N, Ishizawa K, Yamamoto J, Watanabe T, Uike N, Choi I, Terui Y, Usuki K, Nagai H, Uoshima N, Tobinai K
  • Journal Title: Cancer Science 101 Pages: 2059-2064
• [Journal Article] A phase I and pharmacokinetic study of bendamustine hydrochloride in relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma (2010)
  • Author(s): Ogura M, Uchida T, Taniwaki M, Ando K, Watanabe T, Kasai M, Matsumoto Y, Ogawa Y, Ohmachi K, Yokoyama H, Tobinai K.
  • Journal Title: Cancer Science 101 Pages: 2054-2058
  • NAID: 10027831724
• [Journal Article] Phase I and pharmacokinetic study of everolimus (RAD001) in patients with relapsed or refractory non-Hodgkin lymphoma (2010)
  • Author(s): Tobinai K, Ogura M, Maruyama D, Uchida T, Uike N, Choi I, Ishizawa K, Itoh K, Ando K, Taniwaki M, Shimada N, Kobayashi K
  • Journal Title: Int J Hematol 92 Pages: 563-570
• [Journal Article] Characteristics of CD5-positive splenic marginal zone B-cell lymphoma with leukemic manifestation; Clinical, flow cytometry, and histopashological findings of 11 cases (2010)
  • Author(s): Kojima M, Nakamura N, Ohiya D, Tokunaka M, Kikuchi Y, Sato E, Oshimi K, Fujiwara S, Mano H, Murase T, Koike T, Tsunoda S, Matsumoto T, Marutsuka K, Hashimoto Y, Ane M, Ando K
  • Journal Title: J Clin Exp Hematol 50 Pages: 107-112
• [Journal Article] Establishment of xenograft model of human myelodysplastic syndromes (2010)
  • Author(s): Muguruma, et al
  • Journal Title: Hematologica Volume: (in press)
  • Peer Reviewed
• [Journal Article] Bendamustine Is Highly Effective for Relapsed or Refractory Indolent B-Cell Non-Hodgkin Lymphoma (B-NHL) and Mantle Cell Lymphoma (MCL) : Final Results of a Japanese Multicenter Phase II Study (2010)
  • Author(s): Ohmachi, et al
  • Journal Title: Cancer Science Volume: 101 Pages: 2054-2058
  • Peer Reviewed
• [Journal Article] A phase I and pharmacokinetic study of bendamustine hydrochloride in relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma (2010)
  • Author(s): Ogura
  • Journal Title: Cancer Science Volume: 101 Pages: 2054-2058
  • Peer Reviewed
• [Journal Article] Phase I and pharmacokinetic study of everolimus (RAD001) in patients with relapsed or refractory non-Hodgkin lymphoma (2010)
  • Author(s): Tobinaiet, et al
  • Journal Title: Int J Hematol Volume: 92 Pages: 563-570
  • Peer Reviewed
• [Journal Article] Characteristics of CD5-positive splenic marginal zone B-cell lymphoma with leukemic manifestation ; Clinical, flow cytometry, and histopashological findings of 11 cases (2010)
  • Author(s): Kojima, et al
  • Journal Title: J Clin Exp Hemato Volume: 50 Pages: 107-112
  • Peer Reviewed
• [Journal Article] Methotrexate-associated lymphoproliferative disorders mimicking angioimmunoblastic T-cell lymphoma. (2010)
  • Author(s): Hatanaka K., et al
  • Journal Title: Pathology Research and Practice (In press)
  • Peer Reviewed
• [Journal Article] A novel aberrant form of e13a2 BCR-ABL1 transcript in chronic myelogenous leukemia undetectable with the standardized real-time quantitative polymerase chain reaction from the Europe Against Cancer Program (2009)
  • Author(s): Matsushita H, Yamamoto M, Tsuboi K, Masukawa A, Arakawa S, Asai S, Ogawa Y, Ando K, Miyachi H
  • Journal Title: Clinical Chemistry and Laboratory Medicine 47 Pages: 885-887
• [Journal Article] A phase II, open-label, sequential-cohort, dose-escalation study of romiplostim in Japanese patients with chronic immune thrombocytopenic purpura (2009)
  • Author(s): Shirasugi Y, Ando K, Hashino S, Nagasawa T, Kurata Y, Kishimoto Y, Iwato K, Sonehara T, Ohtsu T, Berger D
  • Journal Title: Int J Hematol. 90 Pages: 157-165
  • NAID: 10026108237
• [Journal Article] Phase II study of oral fludarabine in combination with rituximab for relapsed indolent B-cell non-Hodgkin lymphoma (2009)
  • Author(s): Tobinai K, Ishizawa K, Ogura M, Morishima Y, Ando K, Taniwaki M, Watanabe T, Yamamoto J, Uchida T, Nakata M, Terauchi T, Nawano S, Matsusako M, Hayashi M, Hotta T
  • Journal Title: Cancer Sci. 100 Pages: 1951-1956
  • NAID: 10027196034
• [Journal Article] Persistence of derivative chromosome 22 after achieving a major molecular response in chronic myelogenous leukemia with a cryptic BCR-ABL1 fusion gene (2009)
  • Author(s): Matsushita H, Masukawa A, Arakawa S, Ogawa Y, Asai S, Yabe M, Ando K, Miyachi H
  • Journal Title: Int J Hematol. 90 Pages: 623-625
• [Journal Article] Methotrexate-associated lymphoproliferative disorders mimicking angioimmunoblastic T-cell lymphoma (2009)
  • Author(s): Hatanaka K, Nakamura N, Kojima M, Ando K, Irie S, Bunno M, Nakamine H, Uekusa T
  • Journal Title: Pathology Research and Practice 206 Pages: 9-13
• [Journal Article] Phase 1/2 clinical study of dasatinib in Japanese patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia (2009)
  • Author(s): Sakamaki H, Ishizawa K, Taniwaki M, Fujisawa S, Morishima Y, Tobinai K, Okada M, Ando K, Usui N, Miyawaki S, Utsunomiya A, Uoshima N, Nagai T, Naoe T, Motoji T, Jinnai I, Tanimoto N, Miyazaki Y, Ohnishi K, Iida S, Okamoto S, Seriu T, Ohno R
  • Journal Title: Int J Hematol 89 Pages: 332-341
  • NAID: 10025160810
• [Journal Article] A noevel aberrant from of e13a2 BCR-ABL1 transcript in chronic myelogenous Ieukemia undetectable with the standards real-time polymerase chain reaction frim the Europe Against Cancer program (2009)
  • Author(s): Matsusita H., et al
  • Journal Title: Clinical Chemistry and Laboratory Medicine 47 Pages: 885-887
  • Peer Reviewed
• [Journal Article] A phase II, open-label, sequential-cohort, dose-escalation study of romiplostim in Japanese patients with chronic immune thromb ocytenic purpura (2009)
  • Author(s): Shirasugi Y, et al
  • Journal Title: Int J Hematol. 90 Pages: 157-165
  • Peer Reviewed
• [Journal Article] Phase II study of oral fludarabine in combination with retuximab for relapsed indolent B-cell non-Hodgkin lymphoma (2009)
  • Author(s): Tobinai K., et al
  • Journal Title: Cancer Sci. 100 Pages: 1951-1956
  • Peer Reviewed
• [Journal Article] Persistence of derivative chromosome 22 after achieving a major molecular response in chrorlic myelogenous leukemia with a cryptic BCR-ABL1 fusion gene (2009)
  • Author(s): Matsushita H, et al
  • Journal Title: Int J Hematol. 90 Pages: 623-625
  • Peer Reviewed
• [Journal Article] Phase 1/2 clinical study of dasatinib in Japanese patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia.. (2009)
  • Author(s): Sakamaki H., et al
  • Journal Title: Int J Hematol. 89 Pages: 332-341
  • Peer Reviewed
• [Journal Article] Analysis of subjective evaluations on functions of Tele-Coaching Intervention in patients with spinocerebellar degeneration (2008)
  • Author(s): Hayashi A, Kayama M, Ando K, Ono M, Suzukamo Y, Michimata A, Onishi Akiyama M, Fukuhara S, Izumi S
  • Journal Title: NeuroRehabilitation 23 Pages: 159-169
• [Journal Article] Delta-like 4 is indispensable in thymic environment specific for T cell development (2008)
  • Author(s): Hozumi K, Mailhos C, Negishi N, Hirano K, Yahata T, Ando K, Zuklys S, Hollander G, Shima D, Habu S
  • Journal Title: J Exp Med. 205 Pages: 2507-2513
• [Journal Article] C/EBPa and C/EBPe induce monocytic differentiation of myelomonocytic cells with MLL-chimeric fusion gene (2008)
  • Author(s): Matsushita H, Nakajima H, Nakamura Y, Tsukamoto H, Tanaka Y, Asai S, Ono R, Nosaka T, Hotta T, Ando K, Miyachi H.
  • Journal Title: Oncogene 27 Pages: 6749-6760
• [Journal Article] Quiescent human hematopoietic stem cells in the bone marrow niches organize hierarchical structure of hematopoiesis (2008)
  • Author(s): Yahata T, Muguruma Y, Yumino Y, Sheng Y, Uno T, Matsuzawa H, Ito M, Kato S, Ando K
  • Journal Title: Stem Cells 26 Pages: 3228-3236
• [Journal Article] Notch ligand Delta-like 1 expression in stromal cells, but not hematopoietic cells, is essential for marginal zone B cell development (2008)
  • Author(s): Sheng Y, Yahata T, Negishi N, Abe N, Habu S, Hozumi K, Ando K
  • Journal Title: Immunol Lett 121 Pages: 33-37
• [Journal Article] Multicenter prospective trial evaluating the tolerability of imatinib for Japanese patients with chronic myelogenous leukemia in the chronic phase : Does body weight matter? (2008)
  • Author(s): Kanda Y, Okamoto S, Tauchi T, Kizaki M, Inokuchi K, Yabe M, Yokoyama K, Ito Y, Kimura Y, Higashihara M, Bessho M, Ando K, Chiba S, Kurokawa M, Oshimi K, Dan K, Ohyashiki K, Ikeda Y
  • Journal Title: Am J Hematol. 83 Pages: 835-839
• [Journal Article] Delta-like 4 is indispensable in thymic environment specific for T cell development. (2008)
  • Author(s): Hozumi H., et al.
  • Journal Title: Journal of Experimental Medicine 205 Pages: 2507-2513
  • Peer Reviewed
• [Journal Article] Quiescent human hematopoietic stem cells in the bone marrow niches organize the hierarchical structure of hematopoiesis. (2008)
  • Author(s): Yahata T., et al
  • Journal Title: stem Cells 26 Pages: 3228-3236
  • Peer Reviewed
• [Journal Article] Expression of Delta-like 1 in the splenic non-hematopoietic cells is essential for marginal zone B cell development. (2008)
  • Author(s): Sheng Y., et al.
  • Journal Title: Immunology letters 121 Pages: 33-37
  • Peer Reviewed
• [Journal Article] Humanizing bone marrow in immune-deficient mice. (2008)
  • Author(s): Ando K., et al.
  • Journal Title: CURRENT TOPICS IN MICROBIOLOGY AND IMMUNOLOGY 324 Pages: 77-86
• [Presentation] DNA損傷の蓄積はヒト造血幹細胞の自己複製能を制限する (2010)
  • Author(s): 八幡崇
  • Organizer: 日本血液学会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-24
• [Presentation] Notch sugbals regulate hematopoietic hemostasis through osteoblastic nithe meintenance (2010)
  • Author(s): 六車ゆかり
  • Organizer: 日本血液学会
  • Place of Presentation: パシフイコ横浜(神奈川県)
  • Year and Date: 2010-09-24
• [Presentation] 骨芽細胞におけるDelta-like ligand1の発現が骨代謝維持に重要である (2010)
  • Author(s): 六車ゆかり
  • Organizer: 日本骨代謝学会
  • Place of Presentation: 京王プラザホテル(東京都)
  • Year and Date: 2010-07-23
• [Presentation] DNA損傷の蓄積がヒト造血幹細胞の再生能力を低下させる (2010)
  • Author(s): 八幡崇
  • Organizer: 日本サイトメトリー学会
  • Place of Presentation: 東京慈恵医科大学(東京都)
  • Year and Date: 2010-06-26
• [Presentation] DNA損傷の蓄積はヒト造血幹細胞の自己複製能を制限する (2010)
  • Author(s): 八幡崇, 他
  • Organizer: 日本血液学会
  • Place of Presentation: 横浜
• [Presentation] 骨芽細胞におけるDelta-like ligand 1の発現が骨代謝維持に重要である (2010)
  • Author(s): 六車ゆかり, 他
  • Organizer: 日本骨代謝学会
  • Place of Presentation: 東京
• [Presentation] DNA損傷の蓄積がヒト造血幹細胞の再生能力を低下させる (2010)
  • Author(s): 八幡崇, 他
  • Organizer: 日本サイトメトリー学会
  • Place of Presentation: 東京
• [Presentation] DNA損傷によるヒト造血幹細胞の自己複製能の低下 (2009)
  • Author(s): 八幡崇, 他
  • Organizer: 日本血液学会
  • Place of Presentation: 京都
• [Presentation] Importance of Notch signals in hematopoietic homeostasis (2009)
  • Author(s): 六車ゆかり, 他
  • Organizer: The 26^<th> Natio Conference on Osteobiology
  • Place of Presentation: 兵庫県
• [Presentation] ヒト造血幹細胞の造血再生の動態と老化 (2009)
  • Author(s): 八幡崇, 他
  • Organizer: 日本再生医療学会
  • Place of Presentation: 東京
• [Presentation] ヒト造血幹細胞の造血再生の動態と老化 (2009)
  • Author(s): 八幡 崇
  • Organizer: 第8回日本再生医療学会総会
  • Place of Presentation: 東京
• [Presentation] 骨髄異形成症候群のin vivoモデルの確立 (2008)
  • Author(s): 六車ゆかり, 他
  • Organizer: 日本血液学会
  • Place of Presentation: 京都
• [Presentation] 骨髄造血微小環境の恒常性維持におけるJaggedI分子の重要性 (2008)
  • Author(s): 八幡崇, 他
  • Organizer: 日本血液学会
  • Place of Presentation: 京都
• [Presentation] FACSを用いたヒト造血幹細胞の生体内における性状解析 (2008)
  • Author(s): 八幡崇, 他
  • Organizer: 日本サイトメトリー学会
  • Place of Presentation: 東京
• [Presentation] FACSを用いたヒト造血幹細胞の生体内における性伏解析 (2008)
  • Author(s): 八幡 崇, 他
  • Organizer: 第18回日本サイトメトリー学会学術集会
  • Place of Presentation: 東京
• [Presentation] 骨髄造血微小環境の恒常性維持におけるJaggedl分子の重要性 (2008)
  • Author(s): 八幡 崇, 他
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] 骨髄異形成症候群のin vivoモデルの確立 (2008)
  • Author(s): 六車ゆかり, 他
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
• [Book] iPS細胞による鎌状貧血の治療 (2008)
  • Author(s): 八幡 崇
  • Total Pages: 5
  • Publisher: 医薬ジャーナル社