Spermidine metabolism regulates leukemia stem and progenitor cell function through KAT7 expression in patient-derived...

Area of Science:

• Hematology
• Cancer Biology
• Metabolomics

Background:

• Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs), necessitating novel therapeutic targets.
• Understanding metabolic differences between LSCs and normal hematopoietic stem and progenitor cells (HSPCs) is crucial for developing targeted therapies.

Purpose of the Study:

• To define and characterize the distinct metabolome of LSCs compared to HSPCs.
• To investigate the therapeutic potential of targeting specific metabolic vulnerabilities in LSCs.

Main Methods:

• Unbiased mass spectrometry-based metabolomics profiling of primary human LSCs and HSPCs.
• Pharmacological reduction of spermidine and polyamine depletion in vitro and in patient-derived xenografts.
• Mechanistic studies involving protein synthesis inhibition and gene expression analysis (KAT7).

Main Results:

• LSCs exhibit a distinct metabolome compared to HSPCs, with spermidine being significantly enriched in LSCs.
• Pharmacological reduction of spermidine impaired LSC function and reduced leukemic burden in vivo, while sparing HSPCs.
• Spermidine depletion induced LSC differentiation via decreased eIF5A-dependent protein synthesis, involving downregulation of KAT7.

Conclusions:

• Spermidine represents a specific metabolic vulnerability in LSCs.
• Targeting spermidine metabolism offers a promising therapeutic strategy for AML, with potential for rapid clinical translation.