Molecular mechanisms in the pathogenesis of myelodysplastic syndrome

• Project/Area Number: 16KT0113
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Complex Systems Disease Theory
• Research Institution: Kumamoto University
• Principal Investigator: Sashida Goro 熊本大学, 国際先端医学研究機構, 特別招聘教授 (70349447)
• Co-Investigator(Kenkyū-buntansha): 松井 啓隆 熊本大学, 大学院生命科学研究部(医), 教授 (60379849)
• Project Period (FY): 2016-07-19 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2017: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2016: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 骨髄異形成症候群 / 老化 / 造血幹細胞 / クローン造血 / 環境ストレス / DNAメチル化 / ヒストン修飾 / エピゲノム / ストレス / 感染

Outline of Final Research Achievements

Myelodysplastic syndrome, which is more common in the elderly, is a clonal hematopoietic tumor that occurs from hematopoietic stem cells. In order to understand the functional decline of tissue stem cells due to environmental stress over life and the disease onset mechanism, we developed genetic analysis and verification using a mouse biological model in conjunction with analysis using clinical specimens. In this study, the analysis using existing gene expression data also strongly suggested the enhancement of inflammatory stress signal and the involvement in MDS disease state. Based on these findings, in order to prevent the onset of MDS, we have inhibited infection-stress signals as well as remodeled an epigenomic state of MDS stem cells into that of normal hematopoietic stem cells.

Academic Significance and Societal Importance of the Research Achievements

老化による複雑な生物学的応答のもとで、臓器の機能低下やがんを含めた疾患を発症させる機序は明白でない。高齢者に好発する骨髄異形成症候群は造血幹細胞より発生するクローン性造血器腫瘍であり、生涯に渉った環境ストレスによるがん発症の仕組みは不明であった。本研究課題では、MDS幹細胞の遺伝子発現解析データなどの統合的検証によってMDS発症の責任因子を絞り込むとともに、申請者が新たに作製したMDS発症モデルマウスを用いて、MDS発症機序の分子基盤解明を試みた。今後のさらなる研究の展開を図っている。

Research Products

• [Int'l Joint Research] Cincinnati Children's Hospital(米国)
• [Int'l Joint Research] Inner Mongolia University(中国)
• [Int'l Joint Research] Inner Mongolia University(China)
• [Int'l Joint Research] Cincinnati Children's Hospital(米国)
• [Int'l Joint Research] Inner Mongolia University(China)
• [Journal Article] Ezh2 loss propagates hypermethylation at T cell differentiation?regulating genes to promote leukemic transformation (2018)
  • Author(s): Wang Changshan、Oshima Motohiko、Sato Daisuke、Matsui Hirotaka、Kubota Sho、Aoyama Kazumasa、Nakajima-Takagi Yaeko、Koide Shuhei、Matsubayashi Jun、Mochizuki-Kashio Makiko、Nakano-Yokomizo Takako、Bai Jie、Nagao Toshitaka、Kanai Akinori、Iwama Atsushi、Sashida Goro
  • Journal Title: Journal of Clinical Investigation Volume: 128 Issue: 9 Pages: 3872-3886
  • DOI: 10.1172/jci94645
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pathobiologic Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes. (2018)
  • Author(s): Hayashi Y, Zhang Y, Yokota A, Yan X, Liu J, Choi K, Li B, Sashida G, et al.
  • Journal Title: Cancer Discovery Volume: 8 Issue: 11 Pages: 1438-57
  • DOI: 10.1158/2159-8290.cd-17-1203
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ezh1 Targets Bivalent Genes to Maintain Self-Renewing Stem Cells in Ezh2-Insufficient Myelodysplastic Syndrome. (2018)
  • Author(s): Aoyama K, Oshima M, Koide S, Suzuki E, Mochizuki-Kashio M, Kato Y, Tara S, Shinoda D, Hiura N, Nakajima-Takagi Y, Sashida G, Iwama A.
  • Journal Title: iScience Volume: 9 Pages: 161-174
  • DOI: 10.1016/j.isci.2018.10.008
  • Peer Reviewed / Open Access
• [Journal Article] Multifaceted role of the polycomb-group gene EZH2 in hematological malignancies (2017)
  • Author(s): Sashida G, Iwama A
  • Journal Title: Int J Hematol Volume: 105 Issue: 1 Pages: 23-30
  • DOI: 10.1007/s12185-016-2124-x
  • Peer Reviewed
• [Journal Article] Epigenetic dysregulation in myelodysplastic syndromes (2017)
  • Author(s): 指田吾郎
  • Journal Title: Rinsho Ketsueki Volume: 58 Issue: 10 Pages: 1809-1817
  • DOI: 10.11406/rinketsu.58.1809
  • NAID: 130006132647
  • ISSN: 0485-1439, 1882-0824
• [Journal Article] Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome. (2016)
  • Author(s): Hasegawa N, Oshima M, Sashida G, Matsui H, Koide S, Saraya A, Wang C, Muto T, Takane K, Kaneda A, Shimoda K, Nakaseko C, Yokote K, Iwama A.
  • Journal Title: Leukemia Volume: in press Issue: 4 Pages: 861-871
  • DOI: 10.1038/leu.2016.268
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The loss of Ezh2 cooperates with an active JAK2 mutant in the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition. (2016)
  • Author(s): Sashida G, Wang S, Tomioka T, Oshima M, Kazumasa Aoyama K, Kanai A, Mochizuki-Kashio M, Harada H, Shimoda K, Iwama A.
  • Journal Title: J Experimenta l Medicine Volume: 213 Issue: 8 Pages: 1459-1477
  • DOI: 10.1084/jem.20151121
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Hmga2 promotes the development of MDS/MPN in the absence of Tet2 (2018)
  • Author(s): Jie Bai, Takako Yokomizo, Sho Kubota, Atsushi Iwama, Hironori Harada, Goro Sashida
  • Organizer: 日本血液学会
• [Presentation] RUNX3 promotes the development of MDS/MPN overlap syndrome via enhancing expression of Myc in the absence of Tet2 (2017)
  • Author(s): Yokomizo T, Tanaka D, Sho Kubota S, Oshima M, Harada Y, Kanai A, Iwama A, Harada H, Osato M, Sashida G
  • Organizer: American Society of Hematology
  • Int'l Joint Research
• [Presentation] 骨髄異形成症候群におけるエピジェネティック制御の破綻 (2017)
  • Author(s): 指田吾郎
  • Organizer: 日本血液学会
  • Invited
• [Presentation] Role of the Polycomb Methyltransferase Ezh1 in Myelodysplastic Syndrome Induced By Ezh2 Insufficiency (2016)
  • Author(s): Aoyama K, Mochizuki-Kashio M, Oshima M, Koide S, Nakajima-Takagi Y, Maeda M, Sashida G, Iwama A
  • Organizer: American Society of Hematology
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Ezh2 loss promotes the transformation of ETP-ALL via suppressing T-cell differentiation regulators (2016)
  • Author(s): Sashida G, Wang C, Sato D, Oshima M, Matsui H, Nakajima-Takagi Y, Mochizuki-Kashio M, Iwama A
  • Organizer: 日本血液学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] The loss of Ezh2 cooperates with an active JAK2 mutant in the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition (2016)
  • Author(s): Sashida G, Wang C, Oshima M, Aoyama K, Kanai A, Mochizuki-Kashio M, Harada H, Shimoda K, Iwama A
  • Organizer: International Society for Experimental Hematology
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-08-25
  • Int'l Joint Research