ARPP19 promotes MYC expression and associates with patient relapse in acute myeloid leukemia

Abstract

Despite of extensive genetic analysis of acute myeloid leukemia (AML), we still do not understand comprehensively mechanism that promote disease relapse from standard chemotherapy. Based on recent indications for non-genomic inhibition of tumor suppressor protein phosphatase 2A (PP2A) in AML, we examined mRNA expression of PP2A inhibitor proteins in AML patient samples. Notably, out of examined PP2A inhibitor proteins, overexpression of ARPP19 mRNA was found independent of current AML risk classification. Functionally, ARPP19 promoted AML cell viability and expression of oncoproteins MYC, CDK1, and another PP2A inhibitor CIP2A. Clinically, ARPP19 mRNA expression was significantly lower at diagnosis (p=0.035) in patients whose disease did not relapse after standard chemotherapy. ARPP19 was an independent predictor for relapse both in univariable (p=0.007) and in multivariable analyses (p=0.0001); and gave additive information to EVI1 expression and risk group status (additive effect, p=0.005). Low ARPP19 expression also associated with better patient outcome in TCGA LAML cohort (p=0.019). In addition, in matched patient samples from diagnosis, remission and relapse phases, ARPP19 expression associated with disease activity (p=0.034).\n\nTogether, these data identify ARPP19 as a novel oncogenic PP2A inhibitor protein in AML, and demonstrate its risk group independent role in predicting AML patient relapse tendency.