Abstract 786: Genomic and functional characterization identify different manifestations of p53 pathway in 17p13 deletion cases of multiple myeloma.

Abstract

Abstract Multiple myeloma (MM) is an incurable hematologic malignancy. p53, being one of the most commonly mutated tumor suppressor gene in human cancer, is found to be wild type (WT) in almost 90% of MM. Nevertheless, the frequency of p53 abnormalities is more prevalent in the advanced stage of MM, suggesting its crucial role in the disease progression. Of paramount importance, hemizygous deletion of 17p13 (17p13(del)), which harbours the TP53 gene, has been identified in more than 30% of MM patients and is significantly associated with poor prognosis. To date, there is no conclusive evidence that p53 is the critical gene. Essentially, the integrity of p53 pathway in 17p13(del) cases remains obscure. This study utilized three human myeloma cell lines (HMCL) which harbour 17p13(del) encompassing TP53, as study models. Concurrently, HMCLs with various different p53 status (WT, mutation and null) were recruited as reference model. We have identified a spectrum of unique protein expression profile amongst cells with different p53 status upon induction of the pathway. Genotoxic and non-genotoxic stress confer an intact p53 pathway in WT/WT p53 cells; whereas, p53 mutant cells and p53 null cells demonstrated a defective p53 activity, indicating that functional p53 is exclusively required in triggering the downstream response. Using the WT/WT and the mutant/null profile as reference, the three 17p13(del) cell lines exhibited distinctive phenotypes. XG6, which have basal p53 expression half of that of the WT/WT cell line, displayed a partially compromised p53 pathway. Differentially, KMS18, which has a very low level of basal p53, and JJN3 which has a complete absence of basal p53, displayed a virtual abrogation of p53 response, as evidenced by defective transcriptional activities of p53 as well as resistance to growth arrest and apoptosis. Physiological investigations revealed that the remaining single copy of p53 was likely to be negatively regulated by MDM2 overexpression and epigenetic factors. In conclusion, this study has identified different behaviors in the p53 pathway in 17p13(del) cases. p53 appears to possess haploinssufficiency properties whereby hemizygous p53 loss is sufficient to render a partially defective p53 response. p53 basal level was shown to be the critical determinant of the integrity of the pathway. This has significant clinical implications as this finding can be manipulated to identify patients with different outcome and treatment response. Citation Format: Phaik Ju Teoh, Junli Yan, Wee Joo Chng. Genomic and functional characterization identify different manifestations of p53 pathway in 17p13 deletion cases of multiple myeloma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 786. doi:10.1158/1538-7445.AM2013-786