Identification of molecular mechanisms activating hematopoietic stem cells by monitoring expression levels of a new stem-cell marker ESAM

• Project/Area Number: 15K09475
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Osaka University
• Principal Investigator: Takafumi Yokota 大阪大学, 医学系研究科, 講師 (60403200)
• Co-Investigator(Kenkyū-buntansha): 金倉 譲 大阪大学, 医学系研究科, 教授 (20177489) ; 織谷 健司 国際医療福祉大学, 医学部, 教授 (70324762)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 造血幹細胞 / 白血病幹細胞 / ヒト急性骨髄性白血病 / 幹細胞マーカー / 細胞のゆらぎ / ヒト造血幹細胞 / ヒト急性白血病 / 表面抗原

Outline of Final Research Achievements

We previously demonstrated that the endothelial-cell selective adhesion molecule (ESAM) is an important marker of HSCs in humans. In the present study, we have exploited ESAM expression levels as an index to analyze the molecular mechanisms regulating the status of hematopoietic stem cells, and have applied findings to develop new strategies for diagnosis and treatment of human acute leukemia. Our study has revealed that many of human acute myeloid leukemia cases highly expressed ESAM on their tumor cells. We also found that leukemia stem cells (LSCs) represent ESAM expression, of which levels are heterogeneous and are fluctuating at single cell levels according to the proliferating status of LSCs. The TGFβ signaling pathway is autonomously involved in inducing heterogeneity in ESAM expression in the LSC population. The fluctuation is thought to confer certain benefits to LSCs, such as drug resistance and promoting invasiveness.

Research Products

• [Journal Article] Identification of MS4A3 as a reliable marker for early myeloid differentiation in human hematopoiesis. (2018)
  • Author(s): Ishibashi T, Yokota T, Satoh Y, Ichii M, Sudo T, Doi Y, Ueda T, Nagate Y, Hamanaka Y, Tanimura A, Ezoe S, Shibayama H, Oritani K, Kanakura Y.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 3 Pages: 2338-2343
  • DOI: 10.1016/j.bbrc.2017.12.117
  • Peer Reviewed / Open Access
• [Journal Article] リンパ球造血に関する最近の知見 (2017)
  • Author(s): 横田貴史
  • Journal Title: 実験医学 Volume: 35 Pages: 3063-3070
• [Journal Article] 急性リンパ性白血病の遺伝子異常 (2017)
  • Author(s): 横田貴史、金倉譲
  • Journal Title: 血液内科 Volume: 74 Pages: 103-108
  • NAID: 40021065731
• [Journal Article] Endothelial cell-selective adhesion molecule expression in hematopoietic stem/progenitor cells is essential for erythropoiesis recovery after bone marrow injury. (2016)
  • Author(s): Sudo T, Yokota T, Okuzaki D, Ueda T, Ichii M, Ishibashi T, Isono T, Habuchi Y, Oritani K, Kanakura Y.
  • Journal Title: PLoS One Volume: 11 Issue: 4 Pages: e0154189-e0154189
  • DOI: 10.1371/journal.pone.0154189
  • Peer Reviewed / Open Access
• [Journal Article] Genetic abnormalities associated with acute lymphoblastic leukemia (2016)
  • Author(s): Yokota T, Kanakura Y
  • Journal Title: Cancer Science Volume: in press Issue: 6 Pages: 721-725
  • DOI: 10.1111/cas.12927
  • Peer Reviewed / Open Access
• [Journal Article] ESAM is a novel human hematopoietic stem cell marker associated with a subset of human leukemias. (2016)
  • Author(s): Ishibashi T, Yokota T, Tanaka H, Ichii M, Sudo T, Satoh Y, Doi Y, Ueda T, Tanimura A, Hamanaka Y, Ezoe S, Shibayama H, Oritani K, Kanakura Y.
  • Journal Title: Experimental Hematology Volume: 44 Issue: 4 Pages: 269-281
  • DOI: 10.1016/j.exphem.2015.12.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of endothelial antigen ESAM in activated hematopoietic stem cells (2015)
  • Author(s): Sudo T, Yokota T, Kanakura Y
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 5 Pages: 464-474
  • DOI: 10.11406/rinketsu.56.464
  • NAID: 130005076019
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Identification of osteoblast stimulating factor 5 as a negative regulator in the B-lymphopoietic niche. (2015)
  • Author(s): Fujita N, Ichii M, Maeda T, Saitoh N, Yokota T, Yamawaki K, Kakitani M, Tomizuka K, Oritani K, Kanakura Y
  • Journal Title: Experimental Hematology Volume: 43 Issue: 11 Pages: 963-973
  • DOI: 10.1016/j.exphem.2015.07.002
  • Peer Reviewed
• [Presentation] Endothelial Cell-Selective Adhesion Molecule (ESAM) plays important roles in the adult-type hemoglobin synthesis during fetal erythropoiesis (2017)
  • Author(s): Tomoaki Ueda, Takafumi Yokota, Yasuhiro Shingai, Yukiko Doi, Tomohiko Ishibashi, Takao Sudo, Akira Tanimura, Michiko Ichii, Sachiko Ezoe, Hirohiko Shibayama, Kenji Oritani, and Yuzuru Kanakura
  • Organizer: The American Society of Hematology 59th Annual Meeting
  • Int'l Joint Research
• [Presentation] Variable Expression Levels of the Hematopoietic Stem Cell Surface Antigen ESAM Depict Heterogeneity and Fluctuations in Leukemic Stem Cells (2017)
  • Author(s): Yasuhiro Shingai, Takafumi Yokota, Tomoaki Ueda, Yukiko Doi, Tomohiko Ishibashi, Akira Tanimura, Michiko Ichii,Sachiko Ezoe, Hirohiko Shibayama, Kenji Oritani, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 59th Annual Meeting
  • Int'l Joint Research
• [Presentation] SATB1 expression is useful to identify the lymphoid-lineage-biased trajectory of functionally fluctuatinghematopoietic stem cells. (2017)
  • Author(s): Yukiko Doi, Takafumi Yokota, Tomohiko Ishibashi, Yusuke Satoh, Michiko Ichii, Akira Tanimura, Sachiko Ezoe, Hirohiko Shibayama, Kenji Oritani, Yuzuru Kanakura
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Stressed microenvironment induced by 5-FU promotes the proliferation of HSPC in bone marrow (2017)
  • Author(s): Takao Sudo, Takafumi Yokota, Yuzuru Kanakura, Masaru Ishii
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] 造血幹細胞表面抗原ESAMを用いた白血病幹細胞の不均一性とゆらぎの解析 (2017)
  • Author(s): 新開泰宏、横田貴史、上田智朗、土居由貴子、石橋智彦、谷村 朗、一井倫子、江副 幸子、柴山浩彦、織谷健司、金倉 譲
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Endothelial Cell-Selective Adhesion Molecule (ESAM) Is Required for the Ontogeny of Definitive Hematopoietic System in Mice (2016)
  • Author(s): Tomoaki Ueda, Takafumi Yokota, Yasuhiro Shingai, Yukiko Doi, Tomohiko Ishibashi, Takao Sudo, Yasuhiro Nagate, Akira Tanimura, Masahiro Tokunaga, Jiro Fujita, Michiko Ichii, Sachiko Ezoe, Hirohiko Shibayama, Kenji Oritani, and Yuzuru Kanakura
  • Organizer: The American Society of Hematology 58th Annual Meeting
  • Place of Presentation: San Diego (California, USA)
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [Presentation] SATB1 expression helps in identification of the lymphoid-lineage-biased trajectory of functionally fluctuating hematopoietic stem cells (2016)
  • Author(s): Yukiko Doi, Takafumi Yokota, Yusuke Satoh, Tomoaki Ueda, Yasuhiro Shingai, Michiko Ichii, Akira Tanimura, Sachiko Ezoe, Hirohiko Shibayama, Kenji Oritani, Terumi Kohwi-Shigematsu, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 58th Annual Meeting
  • Place of Presentation: San Diego (California, USA)
  • Year and Date: 2016-12-04
  • Int'l Joint Research
• [Presentation] SATB1 expression marks lymphoid-lineage-biased hematopoietic stem cells in mouse bone marrow (2016)
  • Author(s): 土居由貴子, 横田貴史, 石橋知彦, 佐藤友亮, 一井倫子, 谷村 朗, 江副幸子, 柴山浩彦, 織谷健司, 金倉譲
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜 （神奈川県横浜市）
  • Year and Date: 2016-10-14
• [Presentation] Endothelial antigen ESAM is a human HSC marker associated with a subset of human leukemias (2016)
  • Author(s): 石橋知彦, 横田貴史, 田中宏和, 一井倫子, 数藤孝雄, 佐藤友亮, 土居由貴子, 上田智明, 新開泰宏, 谷村 朗, 濱中有理, 江副幸子, 柴山浩彦, 織谷健司, 金倉譲
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜 （神奈川県横浜市）
  • Year and Date: 2016-10-13
• [Presentation] ESAM is required for the ontogeny of definitive hematopoietic system in mice (2016)
  • Author(s): 上田智明, 横田貴史, 土居由貴子, 石橋知彦, 数藤孝雄, 谷村 朗, 徳永正浩, 一井倫子, 江副幸子, 柴山浩彦, 織谷健司, 金倉譲
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜 （神奈川県横浜市）
  • Year and Date: 2016-10-13
• [Presentation] SATB1 expression marks lymphoid-lineage-biased hematopoietic stem cells in mouse bone marrow. (2015)
  • Author(s): Doi Y, Yokota T, Ishibashi1 T, Satoh Y, Ichii M, Tanimura A, Ezoe S, Shibayama H, Oritani K, Kanakura Y.
  • Organizer: The American Society of Hematology 57th Annual Meeting
  • Place of Presentation: The Orange County Convention Center, Orlando, FL, USA
  • Year and Date: 2015-12-06
  • Int'l Joint Research
• [Presentation] ESAM is a novel human hematopoietic stem cell marker associated with a subset of human leukemias. (2015)
  • Author(s): Ishibashi T,Yokota T, Tanaka H, Ichii1 M, Sudo T, Satoh Y, Doi Y, Tanimura A, Hamanaka Y, Ezoe S, Shibayama H, Oritani K, Kanakura Y.
  • Organizer: The American Society of Hematology 57th Annual Meeting
  • Place of Presentation: The Orange County Convention Center, Orlando, FL, USA
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] Endothelial cell-selective adhesion molecule is a novel human hematopoietic stem cell marker associated with a subset of human leukemias (2015)
  • Author(s): Ishibashi T,Yokota T, Tanaka H, Ichii1 M, Sudo T, Satoh Y, Doi Y, Tanimura A, Hamanaka Y, Ezoe S, Shibayama H, Oritani K, Kanakura Y.
  • Organizer: The 44th Annual Scientific Meeting of International Society of Exoerimental Hematology (ISEH)
  • Place of Presentation: Kyoto International Conference Center, Kyoto Japan
  • Year and Date: 2015-09-18
  • Int'l Joint Research
• [Remarks] 大阪大学血液・腫瘍内科ホームページ
  • URL: http://www.hematology.pro/index.html