Journal Article

Expression of p53 N-terminal isoforms in B-cell precursor acute lymphoblastic leukemia and its correlation with clinicopathological profiles

Blanchet, Sandrine, Oh, Lixian, Hainaut, Pierre, Ariffin, Hany

2020

Overview

Background TP53 mutations occur in only about 3% of primary and 10–20% of relapse B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). However, alternative mechanisms may contribute to functionally impairing the p53 pathway in the absence of a mutation. Candidate mechanisms include overexpression of p53 mRNA variants encoding either dominant-negative p53 protein isoforms such as Delta40p53 and Delta133p53, or modulatory isoforms such as p53beta, which counteract the effects of Delta133p53 on replicative senescence in T-lymphocytes. Methods We used semi-quantitative reverse-transcriptase PCR (RT-PCR) and Western blot to investigate the expression of full length p53 (TAp53), Delta40p53, Delta133p53 or p53beta in diagnostic marrow from a clinical cohort of 50 BCP-ALL patients without TP53 mutation (29 males and 21 females, age range 2–14 years) and in the bone marrow cells of 4 healthy donors (used as controls). Results Irrespective of isoforms, levels of p53 mRNA were low in controls but were increased by 2 to 20-fold in primary or relapse BCP-ALL. TAp53 was increased in primary BCP-ALL, Delta40p53 was elevated in relapse BCP-ALL, whereas Delta133p53 and p53beta were increased in both. Next, mRNA levels were used as a basis to infer the ratio between protein isoform levels. This inference suggested that, in primary BCP-ALL, p53 was predominantly in active oligomeric conformations dominated by TAp53. In contrast, p53 mostly existed in inactive quaternary conformations containing ≥2 Delta40 or Delta133p53 in relapse BCP-ALL. Western blot analysis of blasts from BCP-ALL showed a complex pattern of N-terminally truncated p53 isoforms, whereas TAp53beta was detected as a major isoform. The hypothesis that p53 is in an active form in primary B-ALL was consistent with elevated level of p53 target genes CDKN1A and MDM2 in primary cases, whereas in relapse BCP-ALL, only CDKN1A was increased as compared to controls. Conclusion Expression of p53 isoforms is deregulated in BCP-ALL in the absence of TP53 mutation, with increased expression of alternative isoforms in relapse BCP-ALL. Variations in isoform expression may contribute to functional deregulation of the p53 pathway in BCP-ALL, specifically contributing to its down-regulation in relapse forms.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acute lymphoblastic leukemia / Acute lymphocytic leukemia / Analysis / Biochemistry, Molecular Biology / Biomedical and Life Sciences / Biomedicine / Biotechnology / Bone marrow / Bone marrow transplantation / Cancer / Cancer Research / Cell and molecular biology / Cell cycle / Childhood ALL / Chromosomes / Clinical pathology / Diagnosis / Gene expression / Genes / Genetic aspects / Health Promotion and Disease Prevention / Immunoglobulins / Isoforms / Leukemia / Life Sciences / Lymphatic leukemia / Lymphocytes B / Lymphocytes T / MDM2 protein / Medicine/Public Health / MicroRNAs / Molecular biology / Mutation / Oncology / p53 Protein / p53 tumour suppressor protein / Phosphatase / Polymerase chain reaction / Protein isoforms / Proteins / Research Article / Senescence / Software / Statistical analysis / Surgical Oncology / Transplants & implants / Tumor proteins