Novel therapeutics targeting the specified metabolic pathway and transcription factor related to stem cells of chronic myelogenous leukemia
Project/Area Number |
24390244
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Partial Multi-year Fund |
Section | 一般 |
Research Field |
Hematology
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Research Institution | Kyoto University |
Principal Investigator |
MAEKAWA TAIRA 京都大学, 医学(系)研究科(研究院), 教授 (80229286)
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Co-Investigator(Kenkyū-buntansha) |
MIURA Yasuo 京都大学, 医学研究科, 助教 (70605146)
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Co-Investigator(Renkei-kenkyūsha) |
HIRAI Hideyo 京都大学, 医学研究科, 助教 (50315933)
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Project Period (FY) |
2012-04-01 – 2015-03-31
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Project Status |
Completed (Fiscal Year 2014)
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Budget Amount *help |
¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000)
Fiscal Year 2014: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2013: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2012: ¥10,270,000 (Direct Cost: ¥7,900,000、Indirect Cost: ¥2,370,000)
|
Keywords | 白血病幹細胞 / 慢性骨髄性白血病 / 低酸素 / C/EBPβ / 低酸素環境 / 代謝 / 転写因子 / 分子標的治療 |
Outline of Final Research Achievements |
Leukemic stem cell hide in hypoxic bone marrow microenvironment and causes therapy resistance and the recurrence. Chronic myelogenous leukemia (CML) stem cells stay in G0 cell-cycle state. CML stem cells alive in such circumstances independent from BCR-ABL expression, so that they are hard to become the target of tyrosine kinase inhibitors (TKI). We found that transcription factor C/EBPβ acted toward differentiation of CML stem cells, and its expression was low in hypoxia. We hypothesized when the expression of C/EBPβ were low, CML stem cells would remain in the G0 state in hypoxia. We found that interferon α (IFN α), independently from BCR-ABL expression, enhanced the expression of C/EBPβ of CML stem cells through STAT5 pathway. In conclusion, IFN α could drive CML stem cells into cell-cycle state by enhancing their expression of C/EBPβ and differentiate them. These differentiated from CML stem cells proliferate in BCR-ABL dependent fashion, and could become the target of TKI.
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Report
(4 results)
Research Products
(91 results)
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[Journal Article] CCAAT/Enhancer-Binding Protein β Expressed by Bone Marrow Mesenchymal Stromal Cells Regulates Early B-Cell Lymphopoiesis2014
Author(s)
Yoshioka S, Miura Y, Yao H, Satake S, Hayashi Y, Tamura A, Hishita T, Ichinohe T, Hirai H, Takaori-Kondo A, Maekawa T
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Journal Title
Stem Cells
Volume: 32
Issue: 3
Pages: 730-740
DOI
Related Report
Peer Reviewed
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[Journal Article] HAX1 in induced pluripotent stem cells from a patient with severe congenital neutropenia improves defective granulopoiesis.2014
Author(s)
Morishima T, Watanabe K, Niwa A, Hirai H, Saida S, Tanaka T, Kato I, Umeda K, Hiramatsu H, Saito MK, Matsubara K, Adachi S, Kobayashi M, Nakahata T, Heike T
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Journal Title
Haematologica
Volume: 99(1)
Issue: 1
Pages: 19-27
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A Clinical, Pathological and Genetic Characterization of Methotrexate-Associated Lymphoproliferative Disorders.2014
Author(s)
Yamakawa N, Fujimoto M, Kawabata D, Terao C, Nakashima R, Imura Y, Yukawa N, Yoshifuji H, Ohmura K, Fujii T, Yurugi K, Miura Y, Maekawa T, Saji H, Matsuda F, Haga H, Mimori T
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Journal Title
J Rheumatol
Volume: 41
Issue: 2
Pages: 293-299
DOI
Related Report
Peer Reviewed
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[Journal Article] Two Susceptibility Loci to Takayasu Arteritis Reveal a Synergistic Role of the IL12B and HLA-B Regions in a Japanese Population2013
Author(s)
Terao C, Yoshifuji H, Kimura A, Matsumura T, Ohmura K, Takahashi M, Shimizu M, Kawaguchi T, Chen Z, Naruse TK, Sato-Otsubo A, Ebana Y, Maejima Y, Kinoshita H, Murakami K, Kawabata D, Wada Y, Narita I,
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Journal Title
American Journal of Human Genetics
Volume: 93
Issue: 2
Pages: 289-297
DOI
Related Report
Peer Reviewed
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[Journal Article] Significance of semiquantitative assessment of preformed donor-specific antibody using luminex single bead assay in living related liver transplantation2013
Author(s)
Yoshizawa A, Egawa H, Yurugi K, Hishida R, Tsuji H, Ashihara E, Miyagawa-Hayashino A, Teramukai S, Maekawa T, Haga H, Uemoto S
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Journal Title
Clin Dev Immunol
Volume: 2013
Pages: 972705-972705
DOI
Related Report
Peer Reviewed
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[Journal Article] Zoledronic acid significantly enhances radiation induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling.2013
Author(s)
8. Koto K, Murata H, Kimura S, Sawai Y, Horie N, Matsui T, Ryu K, Ashihara E, Maekawa T, Kubo T, Fushiki S.
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Journal Title
Int J Oncol
Volume: 42
Issue: 2
Pages: 525-534
DOI
Related Report
Peer Reviewed
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[Journal Article] Loss of SMAD4 from colorectal cancer cells promotes CCL15 expression to recruit CCR1+ myeloid cells and facilitate liver metastasis.2013
Author(s)
Itatani Y, Kawada K, Fujishita T, Kakizaki F, Hirai H, Matsumoto T, Iwamoto M, Inamoto S, Hatano E, Hasegawa S, Maekawa T, Uemoto S, Sakai Y, Taketo MM
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Journal Title
Gastroenterol
Volume: 145(5)
Issue: 5
Pages: 1064-1075
DOI
NAID
Related Report
Peer Reviewed
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[Journal Article] Myeloid-Derived Suppressor Cells Play Crucial Roles in the Regulation of Mouse Collagen-Induced Arthritis.2013
Author(s)
1. Fujii W, Ashihara E, Hirai H, Nagahara H, Kajitani N, Fujioka K, Murakami K, Seno T, Yamamoto A, Ishino H, Kohno M, Maekawa T, Kawahito Y.
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Journal Title
J Immunol
Volume: 191
Issue: 3
Pages: 1073-1081
DOI
Related Report
Peer Reviewed
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[Journal Article] Association of Takayasu arteritis with HLA-B*67:01 and two amino acids in HLA-B protein.2013
Author(s)
Terao C, Yoshifuji H, Ohmura K, Murakami K, Kawabata D, Yurugi K, Tazaki J, Kinoshita H, Kimura A, Akizuki M, Kawaguchi Y, Yamanaka H, Miura Y, Maekawa T, Saji H, Mimori T
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Journal Title
Rheumatology
Volume: 52(10)
Issue: 10
Pages: 1769-1774
DOI
Related Report
Peer Reviewed
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[Journal Article] Effectiveness of sulforaphane as a radiosensitizer for murine osteosarcoma cells2013
Author(s)
Y. Sawai, H. Murata, M. Horii, K. Koto,T. Matsui, N. Horie, Y. Tsuji, E. Ashihara, T. Maekawa, T. Kubo, S. Fushiki
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Journal Title
Oncol Rep
Volume: 29
Issue: 3
Pages: 941-945
DOI
Related Report
Peer Reviewed
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[Presentation] Essential Roles of C/EBPβ in Survival of Ly6C– monocytes.2014
Author(s)
Tamura A, Hirai H, Yokota A, Sato A, Yao H, Iwasa M, Fujishiro A, Miura Y, Maekawa T
Organizer
American Society of Hematology, 56th Annual Meeting
Place of Presentation
San Francisco, CA, USA
Year and Date
2014-12-08
Related Report
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[Presentation] Protective roles of myeloid-derived suppressor cells in autoimmune arthritis murine models through inhibiting pro-inflammatory immune response of CD4+ T cell.
Author(s)
Fujii W, Nagahara H, Kajitani N, Fujioka K, Murakami K, Nakamura K, Seno T, Yamamoto A, Ishino H, Kohno M, Kawahito Y
Organizer
The 57th Annual General Assemble and Scientific Meeting of the Japan Collage of Rheumatology
Place of Presentation
京都
Related Report
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[Presentation] Myeloid-derived suppressor cells have regulatory roles in mouse collagen-induced arthritis.
Author(s)
Fujii W, Ashihara E, Hirai H, Nagahara H, Fujioka K, Murakami K, Seno T, Yamamoto A, Ishino H, Kohno M, Maekawa T, Kawahito Y
Organizer
Annual European Congress of Rheumatology
Place of Presentation
Madrid, Spain
Related Report
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[Presentation] C/EBPβ expressed by bone marrow mesenchymal stromal cells is indispensable for precursor B-cell lymphopoiesis.
Author(s)
Yoshioka S, Miura Y, Yao H, Iwasa M, Sato A, Tamura A, Yokota A, Hishita T, Ichinohe T, Hirai H, Maekawa T
Organizer
American Society of Hematology, 55th Annual Meeting
Place of Presentation
New Orleans, LA, USA
Related Report
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[Presentation] Cytokine-STATs signalings upregulate endogenous C/EBPβ in BCR-ABL+ leukemic cells independently from BCR-ABL signaling.
Author(s)
Yokota A, Hirai H, Hayashi Y, Tamura A, Sato A, Yao H, Yoshioka S, Iwasa M, Ashihara E, Miura Y, Maekawa T
Organizer
American Society of Hematology, 55th Annual Meeting
Place of Presentation
New Orleans, LA, USA
Related Report
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[Presentation] Cell-intrinsic and -extrinsic involvement of C/EBPβ in the regulation of hematopoietic stem cells.
Author(s)
Tamura A, Hirai H, Hayashi Y, Yokota A, Sato A, Yao H, Yoshioka S, Iwasa M, Ashihara E, Miura Y, Maekawa T
Organizer
American Society of Hematology, 55th Annual Meeting
Place of Presentation
New Orleans, LA, USA
Related Report
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[Presentation] Hypoxia-Adapted Myeloma Cells Possess Stem Cell Character.
Author(s)
shihara E, Nakagawa Y, Yao H, Yokota A, Miura Y, Takata K, Kitamura Y, Hirai H , Maekawa T
Organizer
American Society of Hematology, 55th Annual Meeting
Place of Presentation
New Orleans, LA, USA
Related Report
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[Presentation] Direct Interaction with Bone Marrow Mesenchymal Stromal/Stem Cells Is Required for Hematopoietic Expansion by Parathyroid Hormone.
Author(s)
Yao H, Miura Y, Yoshioka S, Iwasa M, Sato A, Tamura A, Yokota A, Ashihara E, Ichinohe T, Hirai H,Maekawa T
Organizer
American Society of Hematology, 55th Annual Meeting
Place of Presentation
New Orleans, LA, USA
Related Report
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[Presentation] Proliferation and differentiation of hematopoietic cells by osteogenic-induced bone marrow MSCs.
Author(s)
Yao H, Miura Y, Yoshioka S, Iwasa M, Sato A, Hayashi Y, Tamura A, Yokota A, Ichinohe T, Tohyama K, Hirai H, Maekawa T
Organizer
The 75th Annual Meeting of the Japanese Society of Hematology
Place of Presentation
札幌
Related Report
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[Presentation] Involvement of C/EBPβ in the regulation of hematopoietic stem cells.
Author(s)
Tamura A, Hirai H, Hayashi Y, Yokota A, Yao H, Yoshioka S, Sato A, Iwasa M, Ashihara E, Miura Y, and Maekawa T
Organizer
The 75th Annual Meeting of the Japanese Society of Hematology
Place of Presentation
札幌
Related Report
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[Presentation] IL12Bは高安動脈炎の新規疾患感受性遺伝子でありHLA-B*52:01と相互作用を示す
Author(s)
寺尾 知可史、吉藤 元, 木村 彰方, 松村 貴由, 大村 浩一郎, 成瀬 妙子, 佐藤 愛子, 前島 康浩, 和田 庸子, 成田 一衛, 川口 鎮司, 山中 寿, 前川 平, 小川 誠司, 小室 一成, 永井 良三, 田原 康玄, 磯部 光章, 三森 経世, 松田 文彦
Organizer
第41回日本臨床免疫学会
Place of Presentation
下関
Related Report
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