Elevated FOSB-expression; a potential marker of valproate sensitivity in AML.
Histone deacetylase inhibitors (HDIs) are emerging as valuable new agents in the treatment of acute myeloid leukaemia (AML). However, since response rates to these agents alone are low, we sought to identify markers associated with responsiveness. In a trial of 20 patients treated with the HDI sodium valproate (VPA) in combination with all trans retinoic acid and theophylline, three patients responded clinically with one complete remission (CR) and two partial remissions. The in vivo response of the CR patient was mirrored by high in vitro sensitivity of their blasts to VPA, indicating that similar factors determine both in vivo and in vitro sensitivity. Microarray analysis of the primary AMLs and a panel of haemato-lymphoid cell lines, with a similar range of VPA sensitivities as the primary leukaemic blasts, identified elevated FOSB-expression as a potential marker of VPA sensitivity. Quantitative polymerase chain reaction confirmed overexpression of FOSB in the CR patient blasts compared to patients failing to achieve CR, and in a subset of a larger panel of AML samples. Overexpression of FOSB in K562 myeloid cells significantly increased in vitro sensitivity to VPA. Thus, we propose that FOSB is a novel, potential marker of VPA sensitivity in AML.
Khanim
Farhat L
FL
School of Biosciences, University of Birmingham, Birmingham, UK.
Bradbury
Charlotte A
CA
Arrazi
Julie
J
Hayden
Rachel E
RE
Rye
Adam
A
Basu
Supratik
S
MacWhannell
Alan
A
Sawers
Alistair
A
Griffiths
Michael
M
Cook
Mark
M
Freeman
Sylvie
S
Nightingale
Karl P
KP
Grimwade
David
D
Falciani
Francesco
F
Turner
Bryan M
BM
Bunce
Chris M
CM
Craddock
Charles
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D015973:Gene Expression Regulation, Leukemic; D006655:Histone Deacetylases / Q000009:adverse effects*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D014635:Valproic Acid / Q000627:therapeutic use*
D014408:Biomarkers, Tumor; C064269:FOSB protein, human; D016760:Proto-Oncogene Proteins c-fos; D014635:Valproic Acid; D006655:Histone Deacetylases