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Myeloma

p53 haploinsufficiency and functional abnormalities in multiple myeloma

Leukemia volume 28, pages 2066–2074 (2014)Cite this article

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Abstract

Hemizygous deletion of 17p13, which harbors the TP53 gene, has been identified in >10% 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. By utilizing human myeloma cell lines, we showed 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/− and no p53 protein expression, the remaining allele was silenced by promoter hypermethylation. We also developed a p53 target gene signature to summarize the complexity of the p53 pathway abnormalities in MM and showed that it is strongly associated with genomic complexity and patient survival. In conclusion, this study identified TP53 as the critical gene located in 17p13, and revealed its haploinsufficiency properties in MM. Furthermore, we have elucidated that multiple mechanisms can deregulate the p53 functions and that this has important prognostic impact in MM.

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Acknowledgements

WJC is supported by NMRC Clinician Scientist Investigator award. This work is partly supported by Singapore Cancer Syndicate Grant. This research is supported by the National Research Foundation Singapore and the Singapore Ministry of Education under the Research Centers of Excellence initiative. Rafael Fonseca is a Clinical Investigator of the Damon Runyon Cancer Research Fund. This work is supported by grants SPORE CA90297052, P01 CA62242, R01 CA83724, ECOG CA 21115 T, Predolin Foundation, Mayo Clinic Cancer Center and the Mayo Foundation.

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Authors and Affiliations

  1. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    P J Teoh & W J Chng

  2. Cancer Science Institute of Singapore, National University of Singapore, Singapore

    P J Teoh, T H Chung, J Yan & W J Chng

  3. Department of Hematology-Oncology, Mayo Clinic, Scottsdale, AZ, USA

    S Sebastian & R Fonseca

  4. Department of Pathology, National University Cancer Institute of Singapore, National University Health System, Singapore

    S N Choo & S B Ng

  5. Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    S B Ng

  6. Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore

    W J Chng

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Teoh, P., Chung, T., Sebastian, S. et al. p53 haploinsufficiency and functional abnormalities in multiple myeloma. Leukemia 28, 2066–2074 (2014). https://doi.org/10.1038/leu.2014.102

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