Comprehensive exploration of intracellular factors essential for HSC regulation via the CXCL12-CXCR4 axis

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08393
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kyoto University
• Principal Investigator: Aoki Kazunari 京都大学, 医生物学研究所, 助教 (30618020)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: CXCL12 / CXCR4 / cBAF / SMARCA4 / ARID1A / クロマチン / RUNX1 / 転写制御

Outline of Final Research Achievements

It remains unclear how CXCL12 responsiveness is regulated in hematopoietic stem cells and acute leukemic cells. Using a CRISPR screen, we discovered that cBAF regulates the migratory response of human T-ALL cells to CXCL12. cBAF maintains chromatin accessibility genome-widely at RUNX1 binding sites, ensuring RUNX1 binding at these sites, and is required for expression of RUNX1-regulated genes, such as CXCR4 and CDK6; therefore, cBAF inhibition negatively impacts migratory response toward CXCL12 and cell proliferation. These results suggest cBAF as a promising therapeutic target.

Free Research Field

腫瘍学

Academic Significance and Societal Importance of the Research Achievements

cBAFは、T-ALL細胞のCXCL12応答性と細胞自律的増殖を制御しており、T-ALLの有望な治療標的の一つである。急性白血病と呼ばれる血液腫瘍のうち、成人では約5%、小児では約10-15%がT-ALLに分類される。約80%の患者さんで長期生存率が得られているが、残りの患者さんでは治療抵抗性である。今後、有効かつ安全なcBAF機能抑制薬が開発され、T-ALL患者さんの予後の改善に寄与することが期待される。