Protein Phosphatase 2A as a Therapeutic Target in Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a heterogeneous malignant disorder of hematopoietic progenitor cells in which several genetic and epigenetic aberrations have been described. Despite progressive advances in our understanding of the molecular biology of this disease, the outcome for most patients is poor. It is, therefore, necessary to develop more effective treatment strategies. Genetic aberrations affecting kinases have been widely studied in AML; however, the role of phosphatases remains underexplored. Inactivation of the tumor-suppressor protein phosphatase 2A (PP2A) is frequent in AML patients, making it a promising target for therapy. There are several PP2A inactivating mechanisms reported in this disease. Deregulation or specific post-translational modifications of PP2A subunits have been identified as a cause of PP2A malfunction, which lead to deregulation of proliferation or apoptosis pathways, depending on the subunit affected. Likewise, overexpression of either SET or cancerous inhibitor of protein phosphatase 2A, endogenous inhibitors of PP2A, is a recurrent event in AML that impairs PP2A activity, contributing to leukemogenesis progression. Interestingly, the anticancer activity of several PP2A-activating drugs (PADs) depends on interaction/sequestration of SET. Preclinical studies show that pharmacological restoration of PP2A activity by PADs effectively antagonizes leukemogenesis, and that these drugs have synergistic cytotoxic effects with conventional chemotherapy and kinase inhibitors, opening new possibilities for personalized treatment in AML patients, especially in cases with SET-dependent inactivation of PP2A. Here, we review the role of PP2A as a druggable tumor suppressor in AML.

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

“…In AML, SET promotes both malignant growth and drug resistance 17, 26 , and CIP2A inhibition in AML cells reduces proliferation and MYC expression 27 . Prevalent role for PP2A inhibition in AML 10 , and in other cancer types 9, 25 , provides a strong scientific rationale for clinical association between low ARPP19 expression and a lower risk for AML relapse newly discovered in this study. In a direct support of oncogenic role of ARPP19 in AML, we demonstrate that ARPP19 knockdown decreased expression of a well-validated oncogenic PP2A target MYC.…”

“…As some of the PAIPs have been previously associated to AML 10, 17, 18 , but their relatioships to each other are not clear, we used this first study addressing landscape of PAIPs in AML to estimate their expression redundancies and mutual dependencies by Pearson correlation analysis. We found that PME1 levels correlated with CIP2A (Figure 1i, r=0.52, p<0.001), SET (r=0.54, p<0.001) and ARPP19 (r=0.58, p<0.001) expression.…”

“…Decreased PP2A tumor suppressor activity due to an increased expression of PAIPs has been reported to promote malignant growth of several cell types 9, 25 , including leukemic cells 10 . In AML, SET promotes both malignant growth and drug resistance 17, 26 , and CIP2A inhibition in AML cells reduces proliferation and MYC expression 27 .…”

“…Due to recent discovery of PP2A inhibition as a putative AML driver mechanism 10 , PAIPs are also emerging as potentially interesting AML marker genes. However, none of the published studies have compared systematically the expression profiles of different PAIPs in AML.…”

Data mining analysis of the PP2A cell cycle axis in mesothelioma patients

“…Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that regulates by de-phosphorylation several key proteins involved in cell proliferation, apoptosis, and DNA damage response, among others (Arriazu, Pippa, & Odero, 2016). PP2A is an important tumor suppressor, and its inactivation is a crucial step in malignant transformation (Mazhar, Taylor, Sangodkar, & Narla, 2019).…”