Arpp19 Promotes Myc and Cip2a Expression and Associates with Patient Relapse in Acute Myeloid Leukemia.

Eleonora Mäkelä,Otto Kauko,Veli Kairisto,Jukka Westermarck,Urpu Salmenniemi,Eliisa Löyttyniemi,Maija Itälä-Remes,Taru Varila

doi:10.3390/cancers11111774

Abstract

Disease relapse from standard chemotherapy in acute myeloid leukemia (AML) is poorly understood. The importance of protein phosphatase 2A (PP2A) as an AML tumor suppressor is emerging. Therefore, here, we examined the potential role of endogenous PP2A inhibitor proteins as biomarkers predicting AML relapse in a standard patient population by using three independent patient materials: cohort1 (n = 80), cohort2 (n = 48) and The Cancer Genome Atlas Acute Myeloid Leukemia (TCGA LAML) dataset (n = 160). Out of the examined PP2A inhibitors (CIP2A, SET, PME1, ARPP19 and TIPRL), expression of ARPP19 mRNA was found to be independent of the current AML risk classification. Functionally, ARPP19 promoted AML cell viability and expression of oncoproteins MYC, CDK1, and 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 was also associated with better patient outcome in the TCGA LAML cohort (p = 0.019). In addition, in matched patient samples from diagnosis, remission and relapse phases, ARPP19 expression was associated with disease activity (p = 0.034), indicating its potential usefulness as a minimal residual disease (MRD) marker. Together, these data demonstrate the oncogenic function of ARPP19 in AML and its risk group independent role in predicting AML patient relapse tendency.

Highlights

Acute myeloid leukemia (AML) is one of the most aggressive cancer types [1] and up to 85% of the patients under the age of 60 achieve complete remission (CR) after standard induction therapy, only 35% to 40% can be fully cured [1,2]
We found that ARPP19 mRNA expression and its role as a predictive relapse marker was independent of current genetic risk classification schemes, suggesting that ARPP19 mediates its functions in AML by mechanisms that are independent of the known genetic mechanisms
Patient characteristics and distribution of the patients to three clinically used risk groups based on their genetic profiles were representative of an average AML patient population (Supplementary Table S1)

Summary

Introduction

Acute myeloid leukemia (AML) is one of the most aggressive cancer types [1] and up to 85% of the patients under the age of 60 achieve complete remission (CR) after standard induction therapy, only 35% to 40% can be fully cured [1,2]. According to the European Leukemia Net risk group classification, most adult AML patients belong to the intermediate risk group [6] which practically means that they have high relapse. Cancers 2019, 11, 1774 risk after conventional chemotherapy These patients are often directed to hematopoietic stem cell transplantation (HSCT). All intermediate risk patients would not need HSCT but could be cured with intensive chemotherapy. Together with the mortality rate up to 25% among

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Discussion

Conclusion