In:
British Journal of Haematology, Wiley, Vol. 163, No. 5 ( 2013-12), p. 590-602
Kurzfassung:
Chronic lymphocytic leukaemia ( CLL ) is an accumulative disorder marked by deficient apoptosis. The TP 53 homolog TA p63 promotes apoptosis and chemosensitivity in solid tumours and its deregulation may contribute to CLL cell survival. We found that TA p63α was the most prevalent TP 63 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 TP 63 protein expression in B ‐cell lymphoma cell lines. si RNA ‐mediated knockdown of TP 63 resulted in partial protection from spontaneous apoptosis accompanied by reductions in PMAIP 1 ( NOXA ), BBC 3 ( PUMA ), and BAX m RNA in CLL cells and increased proliferation of R aji 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 TP 63 downregulation. MIR21 , known to target TA p63, correlated inversely with TAp63 expression in CLL , and BCR ‐mediated downregulation of TP 63 was accompanied by MIR21 upregulation in most CLL samples. Our data illustrate the pro‐apoptotic function of TP 63, provide insights into the mechanisms of BCR ‐targeting agents, and establish a rationale for designing novel approaches to induce TP 63 in CLL and B ‐cell lymphoma.
Materialart:
Online-Ressource
ISSN:
0007-1048
,
1365-2141
DOI:
10.1111/bjh.2013.163.issue-5
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2013
ZDB Id:
1475751-5
