title: Pro-apoptotic TP53 homolog TAp63 is repressed via epigenetic silencing and B-cell receptor signalling in chronic lymphocytic leukaemia.
abstract: Chronic lymphocytic leukaemia (CLL) is an accumulative disorder marked by deficient apoptosis. The TP53 homolog TAp63 promotes apoptosis and chemosensitivity in solid tumours and its deregulation may contribute to CLL cell survival. We found that TAp63α was the most prevalent TP63 isoform in CLL. Compared to healthy B cells, TAp63 mRNA was repressed in 55·7% of CLL samples. TP63 promoter methylation was high in CLL and inversely correlated with TP63 protein expression in B-cell lymphoma cell lines. siRNA-mediated knockdown of TP63 resulted in partial protection from spontaneous apoptosis accompanied by reductions in PMAIP1 (NOXA), BBC3 (PUMA), and BAX mRNA in CLL cells and increased proliferation of Raji lymphoma cells. TAp63 mRNA levels were higher in CLL with unmutated IGHV. B-cell receptor (BCR) engagement led to repression of TP63 mRNA expression in malignant B cells, while pharmacological inhibition of BCR signalling prevented TP63 downregulation. MIR21, known to target TAp63, correlated inversely with TAp63 expression in CLL, and BCR-mediated downregulation of TP63 was accompanied by MIR21 upregulation in most CLL samples. Our data illustrate the pro-apoptotic function of TP63, provide insights into the mechanisms of BCR-targeting agents, and establish a rationale for designing novel approaches to induce TP63 in CLL and B-cell lymphoma.
authors.affiliation: Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Humphries
authors.forename: J Claire
authors.initials: JC
authors.lastname: Godbersen
authors.forename: Olga V
authors.initials: OV
authors.lastname: Danilova
authors.forename: Prabhjot
authors.initials: P
authors.lastname: Kaur
authors.forename: Brock C
authors.initials: BC
authors.lastname: Christensen
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Danilov
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D063185:Epigenetic Repression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D017154:Stromal Cells; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D011947:Receptors, Antigen, B-Cell; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
keywords: B-cell receptor; TP63; chronic lymphocytic leukaemia; methylation