The protein phosphatase 2A regulatory subunit B55α is a modulator of signaling and microRNA expression in acute myeloid leukemia cells

We recently discovered that the protein phosphatase 2A (PP2A) B55 alpha subunit (PPP2R2A) is under-expressed in primary blast cells and is unfavorable for remission duration in AML patients. In this study, reverse phase protein analysis (RPPA) of 230 proteins in 511 AML patient samples revealed a strong correlation of B55 alpha with a number of proteins including MYC, PKC alpha, and SRC. B55 alpha suppression in OCI-AML3 cells by shRNA demonstrated that the B subunit is a PKC alpha phosphatase. B55 alpha does not target SRC, but rather the kinase suppresses protein expression of the B subunit. Finally, the correlation between B55 alpha and MYC levels reflected a complex stoichiometric competition between B subunits. Loss of B55 alpha in OCI-AML3 cells did not change global PP2A activity and the only isoform that is induced is the one containing B56 alpha. In cells containing B55 alpha shRNA, MYC was suppressed with concomitant induction of the competing B subunit B56 alpha (PPP2R5A). A recent study determined that FTY-720, a drug whose action involves the activation of PP2A, resulted in the induction of B55 alpha In AML cells, and a reduction of the B subunit rendered these cells resistant to FTY-720. Finally, reduction of the B subunit resulted in an increase in the expression of miR-191-5p and a suppression of miR-142-3p. B55 alpha regulation of these miRs was intriguing as high levels of miR-191 portend poor survival in AML, and miR-142-3p is mutated in 2% of AML patient samples. In summary, the suppression of B55 alpha activates signaling pathways that could support leukemia cell survival. (C) 2014 Elsevier B.V.All rights reserved.