TP53 isoform dysregulation in pediatric B-ALL: identifying markers of favorable prognosis and relapse-associated dynamic

TP53 isoforms produced by alternate splicing and promoter usage are shown to play a role in pathogenesis, chemoresistance and relapse in various cancers. Our present study focused on analyzing the expression of different TP53 isoforms in pediatric B cell acute lymphoblastic leukemia (B-ALL).

We performed the transcriptomic analysis of TP53 isoforms expression in publicly available datasets followed by RT-qPCR in our cohort of pediatric B-ALL and correlated with various clinical and hematological parameters.

Transcriptomic data on B-ALL available online showed overexpression of p53α in B-ALL cases at diagnosis while Δ40p53, p53β and Δ133p53 were downregulated in cases at relapse. In our cohort data (n = 99) at diagnosis, we found the upregulation of the long isoform p53α in 65.65% of patients and the short isoforms Δ133p53 in 61.61% patients and Δ40p53 in 27.27% of the patients, respectively. The over-expression of p53γ and p53β was noted in 19.19% and 14.14% of patients, respectively. To check if TP53 gene mutation contributed to this dysregulated isoform expression, we analysed the whole exome data of our B-ALL patients (n = 88). As expected only 3.7% of patients showed mutation in TP53 gene. Further, we analysed the correlation with various clinical parameters and found positive association of Δ133p53 with ETV6::RUNX1 gene fusion (p = 0.032) which is a known marker of good prognosis in B-ALL. To further validate this observation, we enrolled B-ALL relapse cases (n = 46) where samples at diagnosis were also available (n = 12). Analysis of TP53 isoforms expression in relapse B-ALL patients showed significant reduction in the expression of short isoforms of TP53 i.e. Δ133p53 (p = 0.0036) and Δ40p53 (p = 0.032).

Our data show that TP53 isoforms are dysregulated in B-ALL at diagnosis as well as at relapse. Short TP53 isoforms, particularly Δ133p53 is associated with better prognosis suggesting its potential role in refining risk stratification of B-ALL.