Functional analysis of SATB1, a global transcription regulator, in hematopoietic stem cells

• Project/Area Number: 16H05339
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Osaka University
• Principal Investigator: KANAKURA Yuzuru 大阪大学, 大学院医学系研究科, 教授 (20177489)
• Co-Investigator(Kenkyū-buntansha): 横田 貴史 大阪大学, 医学系研究科, 講師 (60403200) ; 土居 由貴子 大阪大学, 医学部附属病院, 医員 (60722288) ; 織谷 健司 国際医療福祉大学, 医学部, 教授 (70324762)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 造血幹細胞 / リンパ球 / クロマチン構造調節蛋白 / リンパ球分化 / 自己複製能力 / 多分化能力 / 老化 / エピジェネティクス

Outline of Final Research Achievements

The population of hematopoietic stem cells (HSCs) consists of a range of cells exhibiting diverse self-renewal and differentiation capabilities. However, the mechanisms underpinning this heterogeneity remain unclear. We studied how Special AT-richsequence binding protein 1 (SATB1), a global genome organizer, is involved in regulating HSC heterogeneity. HSCs from Satb1/Tomato-knockin reporter mice were classified based on SATB1/Tomato intensity, with transplantation experiments revealing stronger differentiation toward the lymphocytic lineage along with high SATB1 levels, whereas SATB1－ HSCs followed the myeloid lineage. Importantly, SATB1－ and SATB1+ HSC populations were interconvertible upon transplantation. Single-cell-transplantation experiments showed heterogeneous reconstitution of HSCs over long period. These results suggest that SATB1 levels regulate the maintenance of HSC multipotency, with variations contributing to HSC heterogeneity.

Academic Significance and Societal Importance of the Research Achievements

造血幹細胞は、全系統の血液細胞に分化する能力と自己複製能力を有し、生涯の造血を支える細胞である。機能的に均一な細胞集団という概念に基づき、高純度で分離する技術が確立されてきたが、最近の研究で高度に純化した造血幹細胞集団も、機能的に不均一な細胞から構成されていることが明らかにされつつある。我々の成果は、リンパ球を産生する能力が高い造血幹細胞の存在を明らかに証明するとともに、それらの分子細胞学的な特徴について、「幹細胞のゆらぎ」の観点から提示した。リンパ球を高率に産生する造血幹細胞の同定は、老化や疾患によって衰える免疫系の機能を回復させる方法につながり、今後の高齢化社会にとって極めて重要である。

Research Products

• [Int'l Joint Research] University of California, San Francisco(米国)
• [Journal Article] Addition of melphalan to fludarabine/busulfan (FLU/BU4/MEL) provides survival benefit for patients with myeloid malignancyfollowing allogeneic bone-marrow transplantation/peripheral blood stem-cell transplantation. (2019)
  • Author(s): Ueda T, Maeda T, Kusakabe S, Fujita J, Fukushima K, Yokota T, Shibayama H, Tomiyama Y, Kanakura Y.
  • Journal Title: International Journal of Hematology Volume: 109 Issue: 2 Pages: 197-205
  • DOI: 10.1007/s12185-018-2562-8
  • Peer Reviewed / Open Access
• [Journal Article] Variable SATB1 Levels Regulate Hematopoietic Stem Cell Heterogeneity with Distinct Lineage Fate (2018)
  • Author(s): Yukiko Doi, Takafumi Yokota, Yusuke Satoh, Daisuke Okuzaki, Masahiro Tokunaga, Tomohiko Ishibashi, Takao Sudo, Tomoaki Ueda, Yasuhiro Shingai, Michiko Ichii, Akira Tanimura, Sachiko Ezoe, Hirohiko Shibayama, Terumi Kohwi-Shigematsu, Junji Takeda, Kenji Oritani, and Yuzuru Kanakura
  • Journal Title: Cell Reports Volume: 23 Issue: 11 Pages: 3223-3235
  • DOI: 10.1016/j.celrep.2018.05.042
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] 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] 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] 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
• [Presentation] ESAM on the Cells of Endothelial Lineage Plays an Important Role in the Development of Definitive Hematopoiesis (2018)
  • Author(s): Tomoaki Ueda, Takafumi Yokota, Yoshihiro Uno, Tomoji Mashimo, Takao Sudo, Tomohiko Ishibashi, Yukiko Doi1, Yasuhiro Shingai, Akira Tanimura, Michiko Ichii, Sachiko Ezoe, Hirohiko Shibayama, Kenji Oritani, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting
  • Int'l Joint Research
• [Presentation] Monitoring ESAM Expression Levels Reveals Autonomous Fluctuation of Leukemia Stem Cells By Autocrine/Paracrine Cytokine Signaling (2018)
  • Author(s): Yasuhiro Shingai, Takafumi Yokota, Takayuki Ozawa, Tomoaki Ueda, Yukiko Doi, Tomohiko Ishibashi, Akira Tanimura, Michiko Ichii, Hirohiko Shibayama, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting
  • Int'l Joint Research
• [Presentation] A Novel Unifrac-Based Analytical Method for Determining Sequential Changes in Gut Microbiota after Hematopoietic Stem Cell Transplantation (2018)
  • Author(s): Shinsuke Kusakabe, Kentaro Fukushima, Tetsuo Maeda, Takafumi Yokota, Ritsuko Nakai, Akihisa Hino, Yasuhiro Nagate, Jiro Fujita, Motooka Daisuke, Shota Nakamura, Hirohiko Shibayama, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting
  • Int'l Joint Research
• [Presentation] Ectonucleosidase CD39 Is Highly Expressed on ATLL Cells and Suppresses the Immune Response through the Adenosine Pathway (2018)
  • Author(s): Yasuhiro Nagate, Sachiko Ezoe, Jiro Fujita, Takafumi Yokota, Michiko Ichii, Akira Tanimura, Yukiko Doi, Tomoaki Ueda, Jun Toda, Hirohiko Shibayama, Kenji Oritani, Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting
  • Int'l Joint Research
• [Presentation] Addition of Melphalan to Fludarabine/Busulfan (FLU/BU4/MEL) Provides Survival Benefit for Patients with Myeloid Malignancy Following Allogeneic Bone Marrow Transplantation/Peripheral Blood Stem Cell Transplantation (2018)
  • Author(s): Tomoaki Ueda, Tetsuo Maeda, Kentaro Fukushima, Jiro Fujita, Shinsuke Kusakabe, Takafumi Yokota, Hirohiko Shibayama, Yoshiaki Tomiyama Yuzuru Kanakura
  • Organizer: The American Society of Hematology 60th Annual Meeting
  • Int'l Joint Research
• [Presentation] クロマチン構造制御蛋白SATB1はリンパ球分化における造血幹細胞の機能的ゆらぎに関与する (2018)
  • Author(s): 土居 由貴子, 横田 貴史, 佐藤 友亮, 石橋 知彦, 数藤 孝雄, 上田 智朗, 新開 泰宏, 小澤 孝幸, 一井 倫子, 谷村 朗, 江副 幸子, 柴山 浩彦, Terumi Kohwi-Shigematsu, 織谷 健司, 金倉 譲
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] B細胞免疫寛容におけるSATB1蛋白の機能的意義について (2018)
  • Author(s): 小澤 孝幸, 横田 貴史, 新開 泰宏, 上田 智朗, 土居 由貴子, 柴山 浩彦, 金倉 譲
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 自分泌/傍分泌サイトカインシグナル伝達を介した白血病幹細胞の自動的ゆらぎ (2018)
  • Author(s): 新開 泰宏, 横田 貴史, 小澤 孝幸, 上田 智朗, 土居 由貴子, 石橋 知彦, 数藤 孝雄, 谷村 朗, 一井 倫子, 江副 幸子, 柴山 浩彦, 金倉 譲
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] ATLL細胞はCD39を高発現し、Adenosine経路を介して免疫応答を抑制する (2018)
  • Author(s): 長手 泰宏, 江副 幸子, 藤田 二郎, 横田 貴史, 一井 倫子, 谷村 朗, 濱中 有理, 土居 由貴子, 上田 智朗, 戸田 淳, 柴山 浩彦, 織谷 健司, 金倉 譲
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 異常なRTKの細胞内輸送阻害は急性骨髄性白血病における有望な治療標的である (2018)
  • Author(s): 頼 晋也, 田中 宏和, 鈴木 麻衣, Luis Espinoza, 谷村 朗, 森田 泰慶, 辰巳 陽一, 横田 貴史, 織谷 健司, 渡邊 俊雄, 金倉 譲, 松村 到
  • Organizer: 第80回日本血液学会学術集会
• [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
• [Remarks] 大阪大学大学院医学系研究科 血液・腫瘍内科学 ホームページ ＞ ニュース
  • URL: http://www.hematology.pro/index/news/article.html?data_id=131
• [Remarks] 大阪大学大学院医学系研究科・医学部ホームページ ＞ 研究活動 ＞ プレスリリース ＞ 2018年
  • URL: http://resou.osaka-u.ac.jp/ja/research/2018/20180613_1
• [Remarks] 大阪大学血液・腫瘍内科ホームページ
  • URL: http://www.hematology.pro/index.html