Prognostic and therapeutic relevance of c‐FLIP in acute myeloid leukaemia. (20th November 2012)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: British journal of haematology. Volume 160:Number 2(2013:Jan.)
• Page Start: 188
• Page End: 198
• Publication Date: 2012-11-20
• Subjects: Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.12108
• Languages: English
• ISSNs: 0007-1048

Abstract

<abstract abstract-type="main" id="bjh12108-abs-0001"> <title>Summary</title> <p>Chemoresistance is a major contributor to the aggressiveness of AML and is often due to insufficient apoptosis. The <italic>CFLAR</italic> gene is expressed as long and short splice forms encoding the anti‐apoptotic proteins c‐FLIP<sub>L</sub> and c‐FLIP<sub>S</sub> (CFLAR<sub>L</sub> and CFLAR<sub>S</sub>, respectively) that play important roles in drug resistance. In univariate analyses of <italic>CFLAR </italic>mRNA expression in adult AML patients, those individuals with higher than median mRNA expression of the long splice form <italic>CFLAR</italic>(L) (but not the short splice form) had significantly lower 3 year overall survival (<italic>P</italic> = 0·04) compared to those with low expression. In cell line studies, simultaneous down‐regulation of c‐FLIP<sub>L</sub> and c‐FLIP<sub>S</sub> proteins using siRNA induced apoptosis in U937 and NB‐4 AML cells, but not K562 or OCI‐AML3 cells. However, dual c‐FLIP<sub>L/S</sub> 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<sub>L</sub> was found to recapitulate the phenotypic effects of dual c‐FLIP<sub>L/S</sub> downregulation. The histone deacetylase (HDAC)1/2/3/6 inhibitor Vorinostat was found to potently down‐regulate c‐FLIP<sub>L</sub> expression by transcriptional and post‐transcriptional mechanisms and to sensitize AML cells to rTRAIL. Further analyses using more selective HDAC inhibitors revealed that HDAC6 inhibition was not required for c‐FLIP<sub>L</sub> down‐regulation. These results suggest that c‐FLIP<sub>L</sub> may have clinical relevance both as a prognostic biomarker and potential therapeutic target for HDAC inhibitors in AML although this requires further study.</p> </abstract>