Analysis of hematopoietic stem cell regulation by numerical chromosome anomaly and the mechanism of MDS pathogenesis

2022 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

血液内科学

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。