Syracuse

Arginine methylation is catalyzed by protein arginine methyltransferases (PRMTs) and is involved in various cellular processes, including cancer development. PRMT2 expression is increased in several cancer types although its role in acute myeloid leukemia (AML) remains unknown. Here, we investigate the role of PRMT2 in a cohort of patients with AML, PRMT2 knockout AML cell lines as well as a Prmt2 knockout mouse model. In patients, low PRMT2 expressors are enriched for inflammatory signatures, including the NF-κB pathway, and show inferior survival. In keeping with a role for PRMT2 in control of inflammatory signaling, bone marrow-derived macrophages from Prmt2 KO mice display increased pro-inflammatory cytokine signaling upon LPS treatment. In PRMT2-depleted AML cell lines, aberrant inflammatory signaling has been linked to overproduction of IL6, resulting from a deregulation of the NF-κB signaling pathway, therefore leading to hyperactivation of STAT3. Together, these findings identify PRMT2 as a key regulator of inflammation in AML.

Arginine methylation of proteins is involved in the regulation of various cellular processes, including DNA repair, gene transcription and posttranscriptional regulation 1 , and is catalyzed predominantly by protein arginine methyltransferases (PRMTs), which transfer a methyl group from S-adenosyl-methionine to the guanidine nitrogen on an arginine residue of the partner protein 2 . In addition to PRMTs, two other arginine methyltransferases have been identified in mammals: NDUFAF7 and METTL23 3 . PRMTs are classified into three types based on their enzymatic activity: type I PRMTs (1, 2, 3, 4, 6, and 8) form ω-N G -monomethylarginine (MMA) and ω-N G ,N G -asymmetric dimethylarginine (ADMA), whereas type II PRMTs (5 and 9) catalyze the production of MMA and ω-N G ,N' G -symmetric dimethylarginine (SDMA). Finally, PRMT7, as the single type III, only produces MMA 4 . In hematological malignancies, PRMTs are major actors in many cellular mechanisms, e.g. proliferation, cell cycle, inhibition of apoptosis, and RNA splicing 5 . Moreover, PRMTs are also involved in controlling gene expression through methylation of arginine residues on histone tails. There are currently phase I/II clinical trials using PRMT inhibitors showing promising results on hematological malignancies, especially acute myeloid leukemia (AML), lymphomas, and myelodysplastic neoplasms 6 .

Among the nine members of the family, PRMT2 is the only one harboring a Src Homology 3 (SH3) binding domain, which is essential for its catalytic activity 7 . Although several partners of PRMT2 have been described, its methylation substrates remain widely unknown 8 . In cancer, PRMT2 expression is upregulated in hepatocellular carcinoma and glioblastoma, and is involved in tumor development 9,10 . Conversely, its expression is decreased in cardia gastric cancer 11 , suggesting potential antitumor activity. We previously identified PRMT2 among other binding partners of the lysine acetyltransferase KAT6A (MOZ) through a double-hybrid screening. As KAT6A is crucial for hematopoiesis and involved in many chromosomal translocations found in AML, it is of high importance to define the precise roles of PRMT2. Indeed, this arginine methyltransferase could have non-