Development of innovative molecular targeted therapeutics based on elucidation of dynamics of CML stem cells in hypoxic environment
Project/Area Number |
16K07171
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Tumor therapeutics
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Research Institution | Kyoto Prefectural Institute of Public Health and Environment (2018) Kyoto University (2016-2017) |
Principal Investigator |
MAEKAWA TAIRA 京都府保健環境研究所, その他部局等, 所長 (80229286)
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Co-Investigator(Kenkyū-buntansha) |
平位 秀世 京都大学, 医学研究科, 助教 (50315933)
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Project Period (FY) |
2016-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
|
Keywords | 慢性骨髄性白血病 / 白血病幹細胞 / インターフェロン / 低酸素環境 / C/EBPβ / 低酸素 / 転写因子 / インターフェロンα / STAT5 / 分子標的治療 |
Outline of Final Research Achievements |
Chronic myelogenous leukemia (CML) has become an era of therapeutic remission and cure with tyrosine kinase inhibitors, and eradication of CML stem cells has become a pressing issue. Interferon (IFN) -α, which was once used as a first-line drug for CML treatment, has unknown mechanisms of action despite its cytogenetic effects in some cases. We attempted to elucidate the dynamics of CML stem cells in a hypoxic environment using hypoxic-adapted CML cell lines and patient cells that are "stem-like". As a result, it was revealed that IFN-α cooperates with BCR-ABL to activate the transcription factor C / EBPβ and induce the differentiation of CML stem cells into myeloid cells and their depletion.
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Academic Significance and Societal Importance of the Research Achievements |
慢性骨髄性白血病の実験動物モデル及び患者から提供を受けた白血病細胞を用いて検討し、インターフェロンが白血病の原因遺伝子と協調して働き、白血病幹細胞の枯渇を誘導することがわかりました。白血病幹細胞は、白血病の治療抵抗性や再発の原因となると考えられており、本研究成果は一部の白血病においてインターフェロンを工夫して投与することによって治療成績がさらに改善する可能性を示唆するものです。
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Report
(4 results)
Research Products
(56 results)
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[Journal Article] C/EBPβ is a critical mediator of IFNα-induced exhaustion of chronic myeloid leukemia stem cells.2019
Author(s)
Yokota A, Hirai H, Sato R, Adachi H, Sato F, Hayashi Y, Sato A, Kamino N, Miura Y, Nakano M, Tenen DG, Kimura S, Tashiro K, Maekawa T
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Journal Title
Blood Advances
Volume: 3
Issue: 3
Pages: 476-488
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] A Rare Case of Adult Autoimmune Neutropenia Successfully Treated with Prednisolone.2017
Author(s)
Fujita M, Kawabata H, Oka T, Hishizawa M, Kitano T, Kondo T, Yamashita K, Yurugi K, Hirai H, Maekawa T, Takaori-Kondo A.
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Journal Title
Intern Med
Volume: 56
Pages: 1415-1419
NAID
Related Report
Peer Reviewed
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[Journal Article] Isolation of mesenchymal stromal/stem cells from cryopreserved umbilical cord blood cells2017
Author(s)
Fujii S, Miura Y, Iwasa M, Yoshioka S, Fujishiro A, Sugino N, Kaneko H, Nakagawa Y, Hirai H, Takaori-Kondo A, Ichinohe T, Maekawa T.
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Journal Title
Journal of Clinical and Experimental Hematopathology
Volume: 57
Issue: 1
Pages: 1-8
DOI
NAID
ISSN
1346-4280, 1880-9952
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Antibodies that React with Liver Tissue and Donor-specific anti-HLA Antibodies in Pediatric Idiopathic Posttransplantation Hepatitis2017
Author(s)
Hirata Y, Yoshizawa A, Egawa H, Ueda D, Okamoto S, Okajima H, Yurugi K, Hishida R, Hirai H, Miyagawa-Hayashino A, Maekawa T, Haga H, Uemoto S
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Journal Title
Transplantation
Volume: 印刷中
Issue: 5
Pages: 1074-1083
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Bortezomib interferes with adhesion of B cell precursor acute lymphoblastic leukemia cells through SPARC up-regulation in human bone marrow mesenchymal stromal/stem cells.2017
Author(s)
Iwasa M, Miura Y, Fujishiro A, Fujii S, Sugino N, Yoshioka S, Yokota A, Hishita T, Hirai H, Andoh A, Ichinohe T, Maekawa T.
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Journal Title
Int J Hematol.
Volume: 105
Issue: 5
Pages: 587-597
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] A clinical trial for Kienbock disease by cultured autologous multipotent mesenchymal stromal cells augmented with vascularized bone grafts: A report of five cases.2017
Author(s)
Ikeguchi R, Aoyama T, Kakinoki R, Ueda M, Kasai Y, Maekawa T, Tada H, Yamamoto M, Matsuda S, Nakamura T, Toguchida J.
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Journal Title
J Orthop Sci.
Volume: 17
Issue: 4
Pages: 30032-30035
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The combination of panobinostat with ponatinib synergistically overcomes imatinib-resistant CML cells.2016
Author(s)
Matsuda Y, Yamauchi T, Hosono N, Uzui K, Negoro E, Morinaga K, Nishi R, Yoshida A, Kimura S, Maekawa T, Ueda T
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Journal Title
Cancer Sci.
Volume: 107
Issue: 7
Pages: 1029-1038
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Genotyping of relapsing polychondritis identified novel susceptibility HLA alleles and distinct genetic characteristics from other rheumatic diseases.2016
Author(s)
Terao C, Yoshifuji H, Yamano Y, Kojima H, Yurugi K, Miura Y, Maekawa T, Handa H, Ohmura K, Saji H, Mimori T, Matsuda F.
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Journal Title
Rheumatology(Oxford)
Volume: 55(9)
Issue: 9
Pages: 1686-92
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Presentation] Impact of Hypothermia on Differentiation and Maturation of Neutrophils.2018
Author(s)
Torikoshi Y, Shime N, Yokota A, Kamio N, Sato A, Shoji T, Kashiwagi T, Miura Y, Maekawa T, Hirai H
Organizer
American Society of Hematology, 60th Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] 生体肝臓移植が施行された胆道閉鎖症の乳幼児に検出された母親に対するHLA 抗体の検討2018
Author(s)
万木紀美子, 岡島英明, 吉澤 淳, 菱田理恵, 小川絵里, 岡本竜弥, 金城昌克, 澁谷江里香, 三浦康生, 上本伸二, 前川 平, 平位秀世
Organizer
第27回 日本組織適合性学会大会
Related Report
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[Presentation] IFNα upregulates C/EBPβ in CD34+ CML stem cells and induces their exhaustion.2017
Author(s)
Yokota A, Hirai H, Sato A, Kamio N, Shoji T, Kashiwagi T, Torikoshi Y, Miura Y, Hayashi Y, Kimura S, Maekawa T
Organizer
第79回日本血液学会学術総会
Related Report
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[Presentation] Late Adherent Subpopulation in Umbilical Cord Blood Has the Same Characteristics and Hematopoiesis-Supporting Capacity As Mesenchymal Stromal/Stem Cells.2016
Author(s)
Yoshioka S, Miura Y, Iwasa M, Fujishiro A, Sugino N, Fujii S, Nakagawa Y, Sato A, Yokota A, Hirai H, Ichinohe T, Takaori-Kondo A, Maekawa T
Organizer
American Society of Hematology, 58th Annual Meeting and Exposition
Place of Presentation
San Diego
Year and Date
2016-12-04
Related Report
Int'l Joint Research
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[Presentation] C/EBPβ is a critical regulator of CML stem cell differentiation and exhaustion induced by interferon-α.2016
Author(s)
Yokota A, Hirai H, Hayashi Y, Sato R, Adachi H, Sato F, Sato A, Tamura A, Iwasa M, Fujishiro A, Shoji T, Kashiwagi T, Kamio N, Torikoshi Y, Miura Y, Nakano M, Tashiro K, Maekawa T
Organizer
The American Society of Hematology 58th Annual Meeting and Exposition
Place of Presentation
San Diego
Year and Date
2016-12-04
Related Report
Int'l Joint Research
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[Presentation] C/EBPβ Is Required for Survival of Ly6C- Monocytes after Committment to Monocyte Lineage through Upregulation of Csf1r.2016
Author(s)
Tamura A, Hirai H, Yokota A, Kamio N, Sato A, Shoji T, Kashiwagi T, Torikoshi Y, Iwasa M, Fujishiro A, Miura Y, Maekawa T
Organizer
American Society of Hematology, 58th Annual Meeting and Exposition
Place of Presentation
San Diego
Year and Date
2016-12-03
Related Report
Int'l Joint Research
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[Presentation] The C/EBPβ transcription factor mediates exhaustion of CML stem cells induced by IFNα2016
Author(s)
Yokota A, Hirai H, Sato A, Tamura A, Shoji T, Kashiwagi T, Fujishiro A,Iwasa M, Miura Y, Hayashi Y, Maekawa T
Organizer
第78回日本血液学会学術総会
Place of Presentation
横浜
Year and Date
2016-10-14
Related Report
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[Presentation] Human bone marrow mesenchymal stromal/sem cells modulate IMiDs-induced differentiation of HSPCs.2016
Author(s)
Fujii S, Miura Y, Iwasa M, Fujishiro A, Sugino N,Sato A, Yokota A, Hirai H,Takaori-Kondo A, Ichinohe T, Maekawa T
Organizer
第78回日本血液学会学術総会
Place of Presentation
横浜
Year and Date
2016-10-13
Related Report
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[Presentation] Stress-induced translational alteration of C/EBPβ isoforms regulates the behavior of HSPCs.2016
Author(s)
Sato A, Hirai H, Yokota A, Tamura A, Shoji T, Kashiwagi T, Iwasa M, Fujishiro A, Miura Y, Ando A, Maekawa T
Organizer
第78回日本血液学会学術総会
Place of Presentation
横浜
Year and Date
2016-10-13
Related Report
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[Presentation] The C/EBPβ transcription factor promotes exhaustion of CML stem cells in response to interferon-α.2016
Author(s)
Yokota A, Hirai H, Hayashi Y, Sato R, Adachi H, Sato F, Sato A, Tamura A, Miura Y, Nakano M, Tashiro K, Maekawa T
Organizer
第75回日本癌学会学術総会
Place of Presentation
横浜
Year and Date
2016-10-07
Related Report
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[Presentation] The C/EBPβ Transcription Factor Mediates the Effect of IFNα on CML Stem Cells Through Promoting Their Differentiation and Exhaustion.2016
Author(s)
Yokota A, Hirai H, Hayashi Y, Sato R, Adachi H, Sato F, Sato A, Tamura A, Iwasa M, Fujishiro A, Shoji T, Kashiwagi T, Miura Y, Nakano M, Tashiro K, Maekawa T
Organizer
The 5th JCA-AACR Special Joint Conference
Place of Presentation
舞浜市
Year and Date
2016-07-14
Related Report
Int'l Joint Research
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