Molecular mechanism for self-renewal of cancer stem cells

• Project Area: Development of Novel Treatment Strategies Targeting Cancer Stem Cells
• Project/Area Number: 22130006
• 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: National Cancer Center Japan
• Principal Investigator: KITABAYASHI Issay 独立行政法人国立がん研究センター, 研究所, 分野長 (20261175)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥181,480,000 (Direct Cost: ¥139,600,000、Indirect Cost: ¥41,880,000); Fiscal Year 2014: ¥33,020,000 (Direct Cost: ¥25,400,000、Indirect Cost: ¥7,620,000); Fiscal Year 2013: ¥34,450,000 (Direct Cost: ¥26,500,000、Indirect Cost: ¥7,950,000); Fiscal Year 2012: ¥35,880,000 (Direct Cost: ¥27,600,000、Indirect Cost: ¥8,280,000); Fiscal Year 2011: ¥35,620,000 (Direct Cost: ¥27,400,000、Indirect Cost: ¥8,220,000); Fiscal Year 2010: ¥42,510,000 (Direct Cost: ¥32,700,000、Indirect Cost: ¥9,810,000)
• Keywords: 白血病 / がん幹細胞 / 分子標的治療 / cancer stem cells / isocitrate dehydrogenase / acute myeloid leukemia / MOZ / MOZ-TIF2 / HoxA9 / M-CSFR / C-Kit / stem cells / 幹細胞 / PU.1 / チロシンキナーゼ阻害剤

Outline of Final Research Achievements

Expression of M-CSFR, HOXA9 and c-KIT is high in stem cells of acute myeloid leukemia (AML). MOZ-fusions induce expression of these genes by interacting with PU.1, c-MYB and BRPF1, respectively, and that these pathways are critical for maintenance of AML stem cells. These finding indicate that the identified pathways can be therapeutic targets for AML.

Research Products

• [Journal Article] IDH2 and NPM1 Mutations Cooperate to Activate Hoxa9/Meis1 and Hypoxia Pathways in Acute Myeloid Leukemia (2015)
  • Author(s): Ogawara Y, Katsumoto T, Aikawa Y, Shima Y, Kagiyama Y, Soga T, Matsunaga H, Seki T, Araki K, Kitabayashi I.
  • Journal Title: Cancer Res. Volume: 75 Issue: 10 Pages: 2005-2016
  • DOI: 10.1158/0008-5472.can-14-2200
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Essential role of PU.1 in maintenance of mixed lineage leukemia-associated leukemic stem cells. (2015)
  • Author(s): Aikawa Y, Yamagata K, Katsumoto T, Shima Y, Shino M, Stanley ER, Cleary ML, Akashi K, Tenen DG, Kitabayashi I.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 3 Pages: 227-236
  • DOI: 10.1111/cas.12593
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ-TIF2 fusion. (2014)
  • Author(s): Shima H, Yamagata K, Aikawa Y, Shino M, Koseki H, Shimada H, Kitabayashi I.
  • Journal Title: Int. J. Hematol. Volume: 99 Issue: 1 Pages: 21-31
  • DOI: 10.1007/s12185-013-1466-x
  • Peer Reviewed
• [Journal Article] Mechanism of PML nuclear body disruption in APL: PML-RARa inhibits PML oligomerization and its phosphorylation restores PML NBs. (2013)
  • Author(s): Shima Y
  • Journal Title: Cancer Res Volume: 73 Issue: 14 Pages: 4278-4288
  • DOI: 10.1158/0008-5472.can-12-3814
  • Peer Reviewed
• [Journal Article] PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies. (2013)
  • Author(s): Iwanami A
  • Journal Title: Proc Natl Acad Sci USA Volume: 110 Issue: 11 Pages: 4339-4344
  • DOI: 10.1073/pnas.1217602110
  • Peer Reviewed
• [Journal Article] MOZ increases p53 acetylation and premature senescence through its complex formation with PML. (2013)
  • Author(s): Rokudai S
  • Journal Title: Proc Natl Acad Sci USA Volume: 110 Issue: 10 Pages: 3895-3900
  • DOI: 10.1073/pnas.1300490110
  • Peer Reviewed
• [Journal Article] Interactomic approach for evaluating nucleophosmin-binding proteins as biomarkers for Ewing's sarcoma. (2013)
  • Author(s): Haga A
  • Journal Title: Electrophoresis Volume: 34 Issue: 11 Pages: 1670-1678
  • DOI: 10.1002/elps.201200661
  • Peer Reviewed
• [Journal Article] Roles of AML1/RUNX1 in T-cell malignancy induced by loss of p53. (2013)
  • Author(s): Shimizu K
  • Journal Title: Cancer Sci. Volume: 104
  • Peer Reviewed
• [Journal Article] β-catenin inhibits promyelocytic leukemia protein tumor suppressor function in colorectal cancer cells. (2012)
  • Author(s): Satow R
  • Journal Title: Gastroenterology Volume: 142 Issue: 3 Pages: 572-581
  • DOI: 10.1053/j.gastro.2011.11.041
  • Peer Reviewed
• [Journal Article] Deregulated transcription factors in leukemia (2011)
  • Author(s): Shima Y, Kitabayashi I
  • Journal Title: Int J Hematol Volume: 28 Pages: 18251-60
  • Peer Reviewed
• [Journal Article] The Hbo1-Brd1/Brpf2 complex is responsible for global acetylation of H3K14 and required for fetal liver erythropoiesis (2011)
  • Author(s): Mishima Y, et al
  • Journal Title: Blood Volume: 118 Pages: 2443-2453
  • Peer Reviewed
• [Journal Article] Proteolytically cleaved MLL subunits are susceptible to distinct degradation pathways (2011)
  • Author(s): Yokoyama A, et al
  • Journal Title: J Cell Sci Volume: 124 Pages: 2208-2219
  • Peer Reviewed
• [Journal Article] Cancer susceptibility polymorphism of p53 at codon 72 affects phosphorylation and degradation of p53 protein. (2011)
  • Author(s): Ozeki C, et al.
  • Journal Title: J Biol Chem Volume: 28 Pages: 18251-60
  • Peer Reviewed
• [Journal Article] PU.1-mediated upregulation of M-CSFR is critical for leukemia stem cell potential induced by MOZ-TIF2. (2010)
  • Author(s): Aikawa Y, et al.
  • Journal Title: Nature Medicine Volume: 16 Pages: 580-585
  • Peer Reviewed
• [Journal Article] A Higher-Order Complex Containing AF4 and ENL Family Proteins with P-TEFb Facilitates Oncogenic and Physiologic MLL-Dependent Transcription. (2010)
  • Author(s): Yokoyama A, et al.
  • Journal Title: Cancer Cell Volume: 17 Pages: 198-212
  • Peer Reviewed
• [Presentation] Epigenetic regulation of stem cells in acute myeloid leukemia (2014)
  • Author(s): 北林一生
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25 – 2014-11-27
  • Invited
• [Presentation] がん幹細胞成立と維持における変異型IDHの役割と治療 (2014)
  • Author(s): 北林一生
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] Clonal evolution of stem cells and therapeutic strategy in acute myeloid leukemia (2014)
  • Author(s): 北林一生
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] Critical pathways for maintenance of stem cells in acute myeloid leukemia (2012)
  • Author(s): Kitabayashi I
  • Organizer: 日本血液学会
  • Place of Presentation: 京都国際会館
  • Year and Date: 2012-10-19
  • Invited
• [Presentation] Pathways critical for maintenance of stem cells in leukemias (2011)
  • Author(s): 北林一生
  • Organizer: 日本分子生物学会
  • Place of Presentation: パシフィコ横浜(招待講演)
  • Year and Date: 2011-12-16
• [Presentation] Pathways critical for maintenance of stem cells in leukemias (2011)
  • Author(s): 北林一生
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋国際会議場(招待講演)
  • Year and Date: 2011-10-04
• [Presentation] Establishment and maintenance of cancer stem cells in MOZ leukemia (2011)
  • Author(s): 北林一生
  • Organizer: USA-Japan Cooperative Cancer Research Workshop
  • Place of Presentation: 神奈川県葉山市
  • Year and Date: 2011-02-24
• [Presentation] Regulation of transcription factors GATA1 and GATA2 by histone acetyltransferase MOZ (2010)
  • Author(s): 北林一生
  • Organizer: 5th International Symposium on GATA factors
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2010-11-17
• [Patent(Industrial Property Rights)] 変異型イソクエン酸デヒドロゲナーゼ１阻害剤としてのイソキサゾール誘導体 (2014)
  • Inventor(s): 北林一生、小川原陽子、他７名
  • Industrial Property Rights Holder: 北林一生、小川原陽子、他７名
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-203475
  • Filing Date: 2014-10-01
• [Patent(Industrial Property Rights)] マウスAMLモデルを用いたイソクエン酸デヒドロゲナーゼ変異体活性の評価システム (2013)
  • Inventor(s): 北林一生、小川原陽子
  • Industrial Property Rights Holder: 北林一生、小川原陽子
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-230472
  • Filing Date: 2013-11-06