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Expression of P53 Protein Isoforms Predicts Survival in Patients with Multiple Myeloma

Abstract

Loss and/or mutation of the TP53 gene are associated with short survival in multiple myeloma, but the p53 landscape goes far beyond. At least 12 p53 protein isoforms have been identified as a result of a combination of alternative splicing, alternative promoters and/or alternative transcription site starts, which are grouped as α, β, γ, from transactivation domain (TA), long, and short isoforms. Nowadays, there are no studies evaluating the expression of p53 isoforms and its clinical relevance in multiple myeloma (MM). We used capillary nanoimmunoassay to quantify the expression of p53 protein isoforms in CD138-purified samples from 156 patients with newly diagnosed MM who were treated as part of the PETHEMA/GEM2012 clinical trial and investigated their prognostic impact. Quantitative real-time polymerase chain reaction was used to corroborate the results at RNA levels. Low and high levels of expression of short and TAp53β/γ isoforms, respectively, were associated with adverse prognosis in MM patients. Multivariate Cox models identified high levels of TAp53β/γ (hazard ratio [HR], 4.49; p < .001) and high-risk cytogenetics (HR, 2.69; p < .001) as independent prognostic factors associated with shorter time to progression. The current cytogenetic-risk classification was notably improved when expression levels of p53 protein isoforms were incorporated, whereby high-risk MM expressing high levels of short isoforms had significantly longer survival than high-risk patients with low levels of these isoforms. This is the first study that demonstrates the prognostic value of p53 isoforms in MM patients, providing new insights on the role of p53 protein dysregulation in MM biology.

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References
1.
Cohen Y, Saranga A, Gatt M, Lavi N, Ganzel C, Magen H . Treatment patterns and clinical outcomes in high-risk newly diagnosed multiple myeloma patients carrying the 17p deletion: An observational multi-center retrospective study. Am J Hematol. 2018; 93(6):810-815. DOI: 10.1002/ajh.25098. View

2.
Nutthasirikul N, Limpaiboon T, Leelayuwat C, Patrakitkomjorn S, Jearanaikoon P . Ratio disruption of the ∆133p53 and TAp53 isoform equilibrium correlates with poor clinical outcome in intrahepatic cholangiocarcinoma. Int J Oncol. 2013; 42(4):1181-8. DOI: 10.3892/ijo.2013.1818. View

3.
Xiong W, Wu X, Starnes S, Johnson S, Haessler J, Wang S . An analysis of the clinical and biologic significance of TP53 loss and the identification of potential novel transcriptional targets of TP53 in multiple myeloma. Blood. 2008; 112(10):4235-46. PMC: 2581979. DOI: 10.1182/blood-2007-10-119123. View

4.
Rosinol L, Oriol A, Rios R, Sureda A, Blanchard M, Hernandez M . Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma. Blood. 2019; 134(16):1337-1345. PMC: 6888142. DOI: 10.1182/blood.2019000241. View

5.
Hafner A, Bulyk M, Jambhekar A, Lahav G . The multiple mechanisms that regulate p53 activity and cell fate. Nat Rev Mol Cell Biol. 2019; 20(4):199-210. DOI: 10.1038/s41580-019-0110-x. View