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Prognostic and therapeutic relevance of c‐ FLIP in acute myeloid leukaemia
Author(s) -
McLornan Donal,
Hay Jodie,
McLaughlin Kirsty,
Holohan Caitriona,
Burnett Alan K.,
Hills Robert K.,
Johnston Patrick G.,
Mills Ken I.,
McMullin Mary Frances,
Longley Daniel B.
Publication year - 2013
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12108
Subject(s) - downregulation and upregulation , cancer research , vorinostat , histone deacetylase inhibitor , apoptosis , flip , romidepsin , biology , medicine , histone deacetylase , histone , gene , genetics
Summary Chemoresistance is a major contributor to the aggressiveness of AML and is often due to insufficient apoptosis. The CFLAR gene is expressed as long and short splice forms encoding the anti‐apoptotic proteins c‐ FLIP L and c‐ FLIP S ( CFLAR L and CFLAR S , respectively) that play important roles in drug resistance. In univariate analyses of CFLAR mRNA expression in adult AML patients, those individuals with higher than median mRNA expression of the long splice form CFLAR ( L ) (but not the short splice form) had significantly lower 3 year overall survival ( P = 0·04) compared to those with low expression. In cell line studies, simultaneous down‐regulation of c‐ FLIP L and c‐ FLIP S proteins using si RNA induced apoptosis in U 937 and NB ‐4 AML cells, but not K 562 or OCI ‐ AML 3 cells. However, dual c‐ FLIP L/S downregulation sensitized all four cell lines to apoptosis induced by recombinant tumour necrosis factor‐related apoptosis‐inducing ligand ( rTRAIL ). Moreover, specific downregulation of c‐ FLIP L was found to recapitulate the phenotypic effects of dual c‐ FLIP L/S downregulation. The histone deacetylase ( HDAC )1/2/3/6 inhibitor V orinostat was found to potently down‐regulate c‐ FLIP L expression by transcriptional and post‐transcriptional mechanisms and to sensitize AML cells to rTRAIL . Further analyses using more selective HDAC inhibitors revealed that HDAC 6 inhibition was not required for c‐ FLIP L down‐regulation. These results suggest that c‐ FLIP L may have clinical relevance both as a prognostic biomarker and potential therapeutic target for HDAC inhibitors in AML although this requires further study.