title: MiR-17-92 represses PTPROt and PP2A phosphatases and amplifies tonic BCR signaling in DLBCL cells.
abstract: B-cell receptor (BCR) signaling plays a pivotal role in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) and targeting the BCR pathway is a highly promising therapeutic strategy in this malignancy. The oncogenic microRNA miR-17-92 modulates multiple cellular processes such as survival, proliferation, apoptosis, angiogenesis, and BCR signaling. In the present study, we identified new targets of miR-17-92, PTPROt (protein phosphatase, receptor type O, truncated) and PP2A (protein phosphatase 2A) phosphatases, which regulate the activity of spleen tyrosine kinase (SYK) and AKT, critical components of BCR signal transduction in DLBCL cells. Introduction of miR-17-92 into DLBCL cells dampened the expression of the PTPROt and PP2A regulatory subunits PPP2R2A (protein phosphatase 2, regulatory subunit B, alpha) and PPP2R5E (protein phosphatase 2, regulatory subunit B, epsilon isoform) and increased the magnitude of SYK and AKT phosphorylation upon BCR ligation. Finally, we found that miR-17-92 expression modulates response to inhibitors of BCR signaling because downregulation of miR-17-92 increased SYK inhibitor-mediated toxicity in DLBCL cells. Our study reveals novel posttranscriptional regulatory pathways that contribute to the deregulation of BCR signaling and modulate SYK inhibitor activity in DLBCL.
authors.affiliation: Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Jablonska
authors.affiliation: Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: Patryk
authors.initials: P
authors.lastname: Gorniak
authors.affiliation: Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Szydlowski
authors.affiliation: Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Sewastianik
authors.affiliation: Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Bialopiotrowicz
authors.affiliation: Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Polak
authors.affiliation: Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Warzocha
authors.affiliation: Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland. Electronic address: pjuszczynski@ihit.waw.pl.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Juszczynski
mesh_terms: D020413:3' Untranslated Regions; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D054648:Protein Phosphatase 2 / Q000235:genetics*; D034622:RNA Interference; D062085:RNA, Long Noncoding; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; C568997:MIR17HG, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D011947:Receptors, Antigen, B-Cell; D054648:Protein Phosphatase 2; C516888:PTPRO protein, human; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3