Loss of PRMT7 reprograms glycine metabolism to selectively eradicate leukemia stem cells in CML

Area of Science:

• Hematology
• Epigenetics
• Cancer Biology

Background:

• Protein arginine methyltransferases (PRMTs) are epigenetic regulators implicated in leukemia progression.
• Leukemia stem cells (LSCs) drive chronic myeloid leukemia (CML) and are critical therapeutic targets.
• PRMT7 exhibits unique functions within the PRMT family, prompting investigation into its role in CML.

Purpose of the Study:

• To investigate the role of PRMT7 in the maintenance and self-renewal of LSCs in CML.
• To evaluate PRMT7 as a potential therapeutic target for CML treatment.

Main Methods:

• Genetic deletion of Prmt7 in a CML mouse model.
• Development and testing of a specific small-molecule PRMT7 inhibitor.
• Analysis of primary human CML CD34+ cells.
• Assessment of effects on LSC self-renewal and normal hematopoiesis.
• Mechanistic studies involving glycine decarboxylase expression and glycine metabolism.

Main Results:

• Targeting PRMT7, via genetic loss or small-molecule inhibition, significantly delayed leukemia development in vivo.
• PRMT7 inhibition impaired LSC self-renewal in both a CML mouse model and primary human CML cells.
• Normal hematopoiesis remained unaffected by PRMT7 targeting.
• Loss of PRMT7 led to reduced glycine decarboxylase expression, reprogramming glycine metabolism to produce methylglyoxal, which is toxic to LSCs.

Conclusions:

• PRMT7 plays a critical role in LSC maintenance and self-renewal in CML.
• Targeting PRMT7 represents a promising therapeutic strategy for eradicating LSCs in CML.
• This study establishes a link between histone arginine methylation and glycine metabolism in the context of CML pathogenesis.