PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia.
Aliaksandra RadzisheuskayaPavel V ShliahaVasily V GrinevEugenia LorenziniSergey KovalchukDaria ShlyuevaVladimir A GorshkovRonald C HendricksonOle Nørregaard JensenKristian HelinPublished in: Nature structural & molecular biology (2019)
Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for multiple malignancies. In this study, we investigated the role of PRMT5 in human acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 and a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. We then identified PRMT5 substrates using multiplexed quantitative proteomics and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5 and that loss of PRMT5 leads to changes in alternative splicing of multiple essential genes. Our study proposes a mechanism for the requirement of PRMT5 for leukemia cell survival and provides potential biomarkers for the treatment response to PRMT5 inhibitors.
Keyphrases
- acute myeloid leukemia
- clinical trial
- induced apoptosis
- emergency department
- endothelial cells
- dna methylation
- cell proliferation
- high resolution
- transcription factor
- gene expression
- single cell
- small molecule
- amino acid
- atomic force microscopy
- endoplasmic reticulum stress
- bioinformatics analysis
- combination therapy
- lymph node metastasis