Biology of p53 protein isoforms and their significance in hematological malignancies

The tumor suppressor gene TP53 produces multiple p53 protein isoforms through alternative promoter usage, messenger RNA splicing, and alternative translation initiation. These isoforms can differentially shape canonical p53 outputs, including cell-cycle arrest, senescence, apoptosis, and DNA-damage responses, and are increasingly recognized as context-dependent regulators of tumor progression and treatment response. However, their roles in hematological malignancies remain incompletely characterized. This review summarizes the structure, biogenesis, and functional consequences of p53 isoforms and integrates available evidence on their expression across acute leukemias, multiple myeloma, chronic lymphocytic leukemia, and selected non-Hodgkin lymphomas. We highlight reported differences between diagnostic and relapse specimens, associations with cytogenetic risk categories, and interactions with TP53 mutation backgrounds. Available data suggest that N-terminally truncated isoforms (Δ40p53, Δ133p53/Δ160p53) and C-terminally spliced variants (p53β/γ) can modulate tetramer composition and downstream transcriptional programs, thereby influencing apoptosis, senescence, and DNA repair. However, the clinical significance of these patterns in hematological malignancies remains incompletely defined because the evidence is derived from relatively small and methodologically heterogeneous studies. More standardized assays and prospective validation in larger, clinically annotated cohorts are needed before p53 isoform profiling can be incorporated into routine risk stratification or therapeutic decision-making. We also discuss methodological advances and limitations in isoform detection at transcript and protein levels, including isoform-specific quantitative reverse-transcription polymerase chain reaction, antibody panels, capillary nanoimmunoassays, and targeted liquid chromatography–tandem mass spectrometry. Comprehensive profiling of p53 isoforms may eventually help refine biological classification and risk assessment, but its clinical utility will depend on assay standardization and prospective validation.