title: The protein phosphatase 2A regulatory subunit B55α is a modulator of signaling and microRNA expression in acute myeloid leukemia cells.
abstract: We recently discovered that the protein phosphatase 2A (PP2A) B55α 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 B55α with a number of proteins including MYC, PKC α, and SRC. B55α suppression in OCI-AML3 cells by shRNA demonstrated that the B subunit is a PKCα phosphatase. B55α does not target SRC, but rather the kinase suppresses protein expression of the B subunit. Finally, the correlation between B55α and MYC levels reflected a complex stoichiometric competition between B subunits. Loss of B55α in OCI-AML3 cells did not change global PP2A activity and the only isoform that is induced is the one containing B56α. In cells containing B55α shRNA, MYC was suppressed with concomitant induction of the competing B subunit B56α (PPP2R5A). A recent study determined that FTY-720, a drug whose action involves the activation of PP2A, resulted in the induction of B55α 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. B55α 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 B55α activates signaling pathways that could support leukemia cell survival.
authors.affiliation: Division of Molecular Hematology, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: pruvolo@mdanderson.org.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Ruvolo
authors.affiliation: Division of Molecular Hematology, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Vivian R
authors.initials: VR
authors.lastname: Ruvolo
authors.affiliation: Division of Molecular Hematology, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jacamo
authors.affiliation: Division of Molecular Hematology, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jared K
authors.initials: JK
authors.lastname: Burks
authors.affiliation: Division of Molecular Hematology, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Division of Molecular Hematology, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Seshagiri R
authors.initials: SR
authors.lastname: Duvvuri
authors.affiliation: Division of Molecular Hematology, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Liran
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Molecular Hematology, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Nianxiang
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Suk Y
authors.initials: SY
authors.lastname: Yoo
authors.affiliation: Division of Molecular Hematology, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rongqing
authors.initials: R
authors.lastname: Pan
authors.affiliation: Division of Molecular Hematology, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Numsen
authors.initials: N
authors.lastname: Hail
authors.affiliation: Division of Molecular Hematology, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: George
authors.initials: G
authors.lastname: Calin
authors.affiliation: Division of Molecular Hematology, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Division of Molecular Hematology, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D000068876:Fingolimod Hydrochloride; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011409:Propylene Glycols / Q000494:pharmacology; D051571:Protein Kinase C-alpha / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C512974:PPP2R2A protein, human; D011409:Propylene Glycols; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D019061:src-Family Kinases; D051571:Protein Kinase C-alpha; D054648:Protein Phosphatase 2; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: AML; B55α; Cell signaling; Relapse; miR-142; miR-191