Analysis of hematopoietic stem cell regulation by numerical chromosome anomaly and the mechanism of MDS pathogenesis
| Project/Area Number |
21K19512
|
|---|
| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
|
|---|
| 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)
|
|---|
| Project Period (FY) |
2021-07-09 – 2023-03-31
|
| Project Status |
Completed (Fiscal Year 2022)
|
| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2022: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
|
|---|
| Keywords | トリソミー8 / 造血幹細胞 / 骨髄異形成症候群 / クロマチン / 数的染色体異常 / 白血病 / トリソミー８ / クローン造血 |
|---|
| Outline of Research at the Start |
骨髄異形成症候群(MDS)は、造血幹細胞より発生する予後不良ながんである。MDSにおいて、トリソミー8などの数的染色体異常は、その予後と密接に関連しており、診断・治療法選択のための重要な判断基準でもある。しかし、その病態基盤は8番染色体上の責任領域・遺伝子を含めて、MDS細胞のゲノム変異・遺伝子発現変動のみの解析では、MDS幹細胞の不均一性もあり明白ではなかった。代表研究者は、人工染色体技術によりヒト8番染色体をマウスES細胞に新たに導入し、+8キメラマウスの作製に成功した。この世界にも類を見ないトリソミー8生体モデルを用いて、トリソミー8による造血幹細胞制御とMDS発症の機序を解明する。
|
| Outline of Final Research Achievements |
Myelodysplastic syndrome (MDS) is a poor prognosis cancer predominantly affecting the elderly that arises from hematopoietic stem cells, leads to hematopoietic failure, and partially transforms into acute myelogenous leukemia. Although it has long been known that numerical chromosome aberrations are involved in the pathogenesis of MDS, the pathogenetic basis of MDS remains unclear. In this study, we generated trisomy 8 chimeric mice, which are unique in the world, and analyzed the pathological basis of MDS development from the viewpoint of chromatin dysregulation. The self-renewal capacity of Trisomy 8 stem cells was reduced compared to the wild type, and their differentiation ability was impaired but not sufficient for MDS development; introduction of a mutation in the RUNX1 gene confirmed the development of MDS in cooperation with Trisomy 8.
|
| Academic Significance and Societal Importance of the Research Achievements |
トリソミー8に限らず、ダウン症を含めたトリソミーによって、年齢依存的にMDSや急性白血病が発症するが、余剰染色体の遺伝子発現だけから、がん化と白血病幹細胞発生の機序や、MDSで観察される全身性炎症の原因は説明できていない。本研究において、トリソミー８造血幹細胞のオミックス解析を実施したところ、トリソミー以外の染色体上の遺伝子発現異常、炎症応答の亢進やクロマチン構造制御の異常が確認できた。今後の解析によって、MDSの病態基盤の理解が進むとともに、新たな標的治療法の開発への進展が期待できる。
|
Report
(3 results)
Research Products
(9 results)
-
-
-
[Journal Article] Exposure to microbial products followed by loss of Tet2 promotes myelodysplastic syndrome via remodeling HSCs2023
Author(s)
Yokomizo-Nakano T, Hamashima A, Kubota S, Bai J, Sorin S, Sun Y, Kikuchi K, Iimori M, Morii M, Kanai A, Iwama A, Huang G, Kurotaki D, Takizawa H, Matsui H, Sashida G.
-
Journal Title
Journal of Experimental Medicine (JEM)
Volume: 220 (7)
Issue: 7
Pages: 9999-9999
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
[Journal Article] The acidic domain of Hmga2 and the domain's linker region are critical for driving self-renewal of hematopoietic stem cell.2022
Author(s)
Sun Y, Kubota S, Iimori M, Hamashima A, Murakami H, Bai J, Morii M, Yokomizo-Nakano T, Osato M, Araki K, Sashida G.
-
Journal Title
Int J Hematol.
Volume: 115
Issue: 4
Pages: 553-562
DOI
Related Report
Peer Reviewed / Int'l Joint Research
-
-
-
-
-
