Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/119618
Title: GENOMIC AND FUNCTIONAL CHARACTERIZATION OF THE P53 PATHWAY IN RELATION TO 17P13 (DEL) IN MULTIPLE MYELOMA
Authors: TEOH PHAIK JU
Keywords: multiple myeloma, p53, 17p13, Nutlin-3, PRIMA-1, ER stress
Issue Date: 13-Aug-2014
Source: TEOH PHAIK JU (2014-08-13). GENOMIC AND FUNCTIONAL CHARACTERIZATION OF THE P53 PATHWAY IN RELATION TO 17P13 (DEL) IN MULTIPLE MYELOMA. ScholarBank@NUS Repository.
Abstract: Hemizygous deletion of 17p13, which harbors the TP53 gene, has been identified in up to 20% of newly diagnosed multiple myeloma (MM) patients and is associated with poor prognosis. To date, there is no conclusive evidence that TP53 is the critical gene. Furthermore, the functional effect of TP53 haploinsufficiency is not well characterized. Herein, we demonstrated that TP53 hemizygous loss was associated with decreased basal expression level with a partially or severely inactivated p53 response upon genotoxic and non-genotoxic stress. The pathway deficiency was manifested as defective p53 transcriptional activities, together with significant resistance to apoptosis. In some cases with p53 WT/- , the remaining allele was silenced by MDM2 over-expression, promoter hypermethylation and/or miRNA deregulation. We also developed a p53 target gene signature summarizing the complexity of the p53 pathway abnormalities in MM and showed that it is strongly associated with genomic instability and patient survival. Importantly, the p53-reactivating drugs, nutlin-3 and PRIMA-1 showed promising therapeutic efficacy in myeloma cells. In conclusion, this study identified important novel biomarkers for p53 deficiency in MM and the potential role of nutlin-3 and PRIMA-1 being novel therapeutic avenues for 17p13(del) patients.
URI: http://scholarbank.nus.edu.sg/handle/10635/119618
Appears in Collections:Ph.D Theses (Open)

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