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- Title
Pro-apoptotic TP53 homolog TAp63 is repressed via epigenetic silencing and B-cell receptor signalling in chronic lymphocytic leukaemia.
- Authors
Humphries, Leigh A.; Godbersen, J. Claire; Danilova, Olga V.; Kaur, Prabhjot; Christensen, Brock C.; Danilov, Alexey V.
- 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 m RNA 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. si RNA-mediated knockdown of TP63 resulted in partial protection from spontaneous apoptosis accompanied by reductions in PMAIP1 ( NOXA), BBC3 ( PUMA), and BAX m RNA in CLL cells and increased proliferation of Raji lymphoma cells. TAp63 m RNA levels were higher in CLL with unmutated IGHV. B-cell receptor ( BCR) engagement led to repression of TP63 m RNA 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.
- Subjects
CHRONIC lymphocytic leukemia treatment; CELL proliferation; GENE expression; B cell receptors; CELLULAR signal transduction; GENE silencing; HOMOLOGY (Biology); APOPTOSIS
- Publication
British Journal of Haematology, 2013, Vol 163, Issue 5, p590
- ISSN
0007-1048
- Publication type
Article
- DOI
10.1111/bjh.12580