siRNA targeting the IRF2 transcription factor inhibits leukaemic cell growth.
Interferon regulatory factor (IRF) 1 and its functional antagonist IRF2 were originally discovered as transcription factors that regulate the interferon-beta gene. Control of cell growth has led to the definition of IRF1 as a tumour suppressor gene and IRF2 as an oncogene. Clinically, approximately 70% of cases of acute myeloid leukaemia demonstrate dysregulated expression of IRF1 and/or IRF2. Our previous studies have shown that human leukaemic TF-1 cells exhibit abnormally high expression of both IRF1 and IRF2, the latter acting to abrogate IRF1 tumour suppression, making these cells ideal for analysis of down-regulation of IRF2 expression. A novel G418 screening protocol was developed and used for identifying effective siRNA that targets IRF2 (siIRF2). Using optimized siIRF2 in leukaemic TF-1 cells, IRF2 was down-regulated by approximately 70% at both mRNA and protein levels. Phenotypically, this resulted in growth inhibition associated with G2/M arrest as well as induction of polyploidy, differentiation and apoptosis. In contrast to these results, siIRF2 targeting did not affect normal haematopoietic stem/progenitor cell growth. These results indicate the potential utility of IRF2 inhibition as a therapeutic approach to cancer.
Children's Cancer Institute Australia for Medical Research, Randwick, Australia.
Ailyn
A
Choo
Patricia
P
Palladinetti
Tiffany
T
Holmes
Shreerupa
S
Basu
Sylvie
S
Shen
Richard B
RB
Lock
Tracey A
TA
O'Brien
Geoff
G
Symonds
Alla
A
Dolnikov
D018952:Antigens, CD34 / Q000032:analysis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D006410:Hematopoiesis; D006801:Humans; D050836:Interferon Regulatory Factor-2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D007938:Leukemia / Q000473:pathology / Q000628:therapy*; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D034741:RNA, Small Interfering / Q000235:genetics*
D018952:Antigens, CD34; C494229:IRF2 protein, human; D050836:Interferon Regulatory Factor-2; D018950:Lipopolysaccharide Receptors; D034741:RNA, Small Interfering