Therapeutic Re-Activation of Protein Phosphatase 2A in Acute Myeloid Leukemia

Abstract

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that is required for normal cell growth and development. PP2A is a potent tumor suppressor, which is inactivated in cancer cells as a result of genetic deletions and mutations. In myeloid leukemias, genes encoding PP2A subunits are generally intact. Instead, PP2A is functionally inhibited by post-translational modifications of its catalytic C subunit, and interactions with negative regulators by its regulatory B and scaffold A subunits. Here, we review the molecular mechanisms of genetic and functional inactivation of PP2A in human cancers, with a particular focus on human acute myeloid leukemias (AML). By analyzing expression of genes encoding PP2A subunits using transcriptome sequencing, we find that PP2A dysregulation in AML is characterized by silencing and overexpression of distinct A scaffold and B regulatory subunits, respectively. We review the mechanisms of functional PP2A activation by drugs such as fingolimod, forskolin, OP449, and perphenazine. This analysis yields two non-mutually exclusive mechanisms for therapeutic PP2A re-activation: (i) allosteric activation of the phosphatase activity, and (ii) stabilization of active holo-enzyme assembly and displacement of negative regulatory factors from A and B subunits. Future studies should allow the development of specific and potent pharmacologic activators of PP2A, and definition of susceptible disease subsets based on specific mechanisms of PP2A dysregulation.

Keywords: enzyme activation; gene expression; kinase signaling; leukemia; protein phosphatase 2A.

Figure 1

Human acute myeloid leukemia cells exhibit distinct alterations in the expression of specific genes encoding PP2A subunits. Relative expression of genes encoding PP2A subunits (catalytic C subunits in red, scaffold A subunits in blue, and regulatory B subunits in black) measured as a ratio of expression in AML cells relative to normal CD34+ bone marrow hematopoietic progenitor cells in normalized read counts. PPP2R2C and PPP2R3B are not significantly expressed and thus not shown, whereas PPP2R1B, PPP2R2B, and PPP2R5B are statistically significantly altered in their expression in AML cells relative to normal CD34+ cells (Benjamini Hochberg-adjusted p < 0.05).