Functional significance of Cebpb in metabolic rewiring during transformation and its application to the novel therapeutic approaches

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08379
• 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: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Yokota Asumi 東京薬科大学, 生命科学部, 助教 (00571556)
• Co-Investigator(Kenkyū-buntansha): 平位 秀世 東京薬科大学, 生命科学部, 教授 (50315933)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 転写因子 / C/EBPβ / 細胞分化 / 細胞増殖 / 造血器腫瘍

Outline of Final Research Achievements

The transcription factor C/EBPβ is induced in hematopoietic stem and progenitor cells in response to stimuli such as inflammation and promotes the proliferation of hematopoietic stem and progenitor cells and their differentiation into myeloid cells. In this study, we found that the expression of C/EBPβ was elevated in the hematopoietic stem and progenitor cells of the Flt3-ITD knock-in mouse hematopoietic tumor model, and that the deficiency of the Cebpb gene markedly suppressed the pathology of leukemia. Additionally, while Flt3-ITD enhanced the self-renewal and proliferation abilities of hematopoietic stem and progenitor cells, these abilities were significantly abrogated by the deficiency of Cebpb. Mechanistically, it was suggested that the activation of lipid metabolism-related genes by Flt3-ITD could be the target of C/EBPβ in the formation of leukemia pathology.

Free Research Field

血液学

Academic Significance and Societal Importance of the Research Achievements

本研究では、急性骨髄性白血病において認められ、腫瘍形成に寄与するFLT3-ITD変異によって、転写因子C/EBPβの発現亢進が誘導されること、また炎症経路や脂質代謝経路の活性化を介して、C/EBPβが腫瘍幹細胞の自己複製や増殖を制御しており、病態形成・進展に重要であることを示した。FLT3-ITD陽性白血病に対しては、FLT3阻害剤が初発例から用いられるようになり、予後を改善したが、薬剤耐性や治療抵抗性の問題もあり、治療成績改善は喫緊の課題である。本研究によって、C/EBPβまたC/EBPβが制御する下流経路の重要性を示したことは、新規治療アプローチの開発に繋がる重要な知見となると考える。