Effect of FTY720 on gene expression in KMT2A-R AML cell line THP1

KMT2A-rearranged (KMT2A-R)- leukemia is a distinct and rare form of leukemia which mostly affects children. Despite extensive research, KMT2A-R-patients have a dismal prognosis and no targeted therapy is yet available in the clinics. SET is a potent oncoprotein and an endogenous inhibitor of the phosphatase PP2A. In this study we show that SET is specifically enriched in KMT2A-R-leukemic stem cells (LSCs) and it is essential for the self-renewal of KMT2A-R-cells. Treatment with SET-PP2A inhibitor FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest, cellular death and increased sensitivity to chemotherapy treatment in KMT2A-R-models. Genetic and pharmacological inhibition of SET via FTY720 led to down-regulation in the expression of several genes belonging to the KMT2A-R-leukemia signature, including MYC, HOXA10 and HOXA9/MEIS1 target genes. Taken together these results demonstrated that SET represents an interesting and novel player of KMT2A-R-leukemia and its antagonism through FTY720 could serve as a novel strategy to treat this disease. We treated the KMT2A-R cell line THP1 with either vehicle (DMSO) or FTY720 (5uM) for 24hr and collected RNA for RNAseq. Every sample was run in triplicate.