An analysis of the clinical and biologic 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, Fenghuang Zhan

Research output: Contribution to journalArticlepeer-review

118 Scopus citations

Abstract

TP53 is a tumor suppressor gene that functions as transcriptional regulator influencing cellular responses toDNAdamage. Here we explored the clinical and transcriptional effects of TP53 expression in multiple myeloma (MM). We found that low expression of TP53, seen in approximately10%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 vs -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 overexpressed TP53 in 4 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 2 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 probably 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.

Original languageEnglish
Pages (from-to)4235-4246
Number of pages12
JournalBlood
Volume112
Issue number10
DOIs
StatePublished - 15 Nov 2008
Externally publishedYes

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