Submitted October 25, 2007
Accepted February 6, 2008
An analysis of the clinical and biological significance of TP53 loss and the identification of potential novel transcriptional targets of TP53 in multiple myeloma
Wei Xiong, Xiaosong Wu, Sarah Starnes, Sarah K Johnson, Jeff Haessler, Siqing Wang, Lijuan Chen, Bart Barlogie, John D Shaughnessy Jr, and Fenghuang Zhan*
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AK
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AK
Cancer Research and Biostatistics, Seattle, WA
* Corresponding author; email: zhanfenghuang{at}uams.edu.
TP53 is a tumor suppressor gene that functions as transcriptional regulator influencing cellular responses to DNA damage. Here, we explored the clinical and transcriptional effects of TP53 expression using multiple myeloma (MM) as model. We found that low-expression of TP53 in MM, seen in approximately 10-20% of newly diagnosed patients, is highly correlated with TP53 deletion, an inferior clinical outcome, and represents an independent risk factor. Analysis of the expression of 122 known TP53 target genes in TP53-high versus -low MM cells from 351 newly diagnosed cases, revealed that only a few were highly correlated with TP53 expression. To elucidate TP53 regulatory networks in MM, we over-expressed TP53 in four MM cell lines. Gene expression profiling of these cell lines detected 85 significantly differentially expressed genes with 50 up-regulated and 35 down-regulated. Unsupervised hierarchical clustering of myeloma samples from 351 newly diagnosed and 90 relapsed patients using the 85 putative TP53 target genes, revealed two major subgroups showing a strong correlation with TP53 expression and survival. These data suggest that loss of TP53 expression in MM confers high risk and likely results in the deregulation of a novel set of MM-specific TP53-target genes. TP53 target gene specificity may be unique to different cell lineages.
