Metabolic reprogramming of leukemia stem cells by hematopoietic transcription factors

• Project/Area Number: 17K16192
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Yokohama City University
• Principal Investigator: TAKAHASHI HIROYUKI 横浜市立大学, 医学研究科, 客員研究員 (20737712)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 白血病幹細胞 / MLL白血病 / 細胞内代謝 / リプログラミング / 代謝リプログラミング / 解糖系 / 癌 / 細胞・組織

Outline of Final Research Achievements

It has been reported that the function of leukemia stem cells (LSCs) is regulated by various factors such as transcription factors, epigenetic regulators and intracellular signaling. However, precise mechanism how these molecules regulate LSC function remains unclear. We herein examined a role of hematopoietic transcription factors in regulating self-renewal capacity of LSCs using MLL-ENL leukemia as a model. We found that PU.1 is absolutely required for LSC function of MLL leukemia. Transcriptome analysis revealed that PU.1 regulates various glycolytic enzymes, and loss of PU.1 leads to a global changes in metabolic landscape of LSCs.

Academic Significance and Societal Importance of the Research Achievements

本研究により、PU.1がMLL白血病のLSC制御において必須の役割を果たしていることが明らかとなった。さらにPU.1はLSCにおける代謝制御に重要な役割を果たしており、これによってLSCが維持されている可能性が明らかとなった。
以上の成果は、MLL白血病においてPU.1とその下流経路が治療の良い標的となることを示しており、将来的な新規治療薬開発に役立つものと期待される。