PRMT1-mediated FLT3 arginine methylation promotes maintenance of FLT3-ITD+ Acute Myeloid Leukemia

The presence of FLT3-ITD mutations in patients with acute myeloid leukemia (AML) is associated with poor clinical outcome. FLT3 tyrosine kinase inhibitors (TKIs), although effective in kinase ablation, do not eliminate primitive FLT3-ITD + leukemia cells, which are potential sources of relapse. Thus understanding mechanisms underlying FLT3-ITD + AML cell persistence is essential to devise future AML therapies. Here, we show that expression of PRMT1, the primary type I arginine methyltransferase, significantly increases in AML cells relative to normal hematopoietic cells. Genome-wide analysis, co-immunoprecipitation assay and PRMT1 KO mouse studies indicate that PRMT1 preferentially cooperates with FLT3-ITD contributing to AML maintenance. Genetic or pharmacological inhibition of PRMT1 markedly blocked FLT3-ITD + AML cell maintenance. Mechanistically, PRMT1 catalyzed FLT3-ITD protein methylation at arginine 972/973, and PRMT1 promoted leukemia cell growth in a FLT3 methylation-dependent manner. Moreover, effects of FLT3-ITD methylation in AML cells were partially due to crosstalk with FLT3-ITD phosphorylation at tyrosine 969 (Y969). Importantly, FLT3 methylation persisted in FLT3-ITD + AML cells following kinase inhibition, indicating that methylation occurs independently of kinase activity. Finally, in both patient-derived xenograft (PDX) and murine AML models, combined administration of AC220 with a type I PRMT inhibitor (MS023) enhanced elimination of FLT3-ITD + AML cells relative to AC220 treatment alone. Our study demonstrates that PRMT1-mediated FLT3 methylation promotes AML maintenance and suggests that combining PRMT1 inhibition with FLT3 TKI treatment could be a promising approach to eliminate FLT3-ITD + AML cells.