P53 Tumor suppressor gene in chronic myelogenous leukemia: a sequential study

Abstract

Loss of the p53 gene alleles was investigated in 26 patients with Ph+, BCR/ABL+ chronic myeloid leukemia (CML) by means of the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis using the restriction enzyme AccII. In all cases, peripheral blood and/or bone marrow samples were obtained at different times during the chronic phase of the disease and at blast crisis, and in some of them also at the accelerated phase. Of the 12 cases considered informative, 11 evolved into myeloid type blast crisis and one into a lymphoid blast crisis, whereas only two showed an i(17q) chromosome at cytogenetic study. In four of the 12 informative cases, a loss of one p53 gene allele was observed, in all cases coincident with the development of the accelerated phase or blast crisis. One patient with a deleted p53 gene allele, in whom it was possible to analyze the gene structure in the three CML evolutive phases (chronic and accelerated phases and blast crisis), showed loss of the p53 gene allele in both the accelerated and the blastic phase, but not during the chronic phase. On the other hand, one of the two cases with an i(17q) chromosome exhibited one allelic deletion of the p53 gene. Thus, the relatively frequent monoallelic deletion of the p53 gene coincident with the appearance of the blast crisis registered in the present study would support a possible role of the p53 gene alterations in the evolution of CML to its final stages.

BCR/ABL Recruits p53 Tumor Suppressor Protein to Induce Drug Resistance

“…Survival mechanisms associated with p53 activation may be especially relevant because almost all CML-CP and about 70-85% of CML-BC cases are expected to retain wild-type p53. [76][77][78][79] It can be postulated that each type of neoplastic cell offers a particular environment in which p53 might generate different effects. For example, elevated expression of p53 in 32Dcl3 hematopoetic cell line transformed by v-ABL manifested a reduction in growth rate, while the v-SRC-transformed cells underwent differentiation.…”

The Clinical Significance of Mutations of the P52 Tumour Suppressor Gene in Haematological Malignancies

“…P53 point mutations are generally associated with loss of the other P53 allele, through 17p deletion. In CML, as seen above, several case reports have suggested that loss of a P53 allele preceded the presence of a detectable P53 point mutation Rovira et al, 1995). In a large series of MALT lymphoma, of the 11 low-grade tumours which showed P53 abnormalities, only one showed the concomitance of P53 mutation and allele loss, whereas, in high-grade tumours, six of nine affected cases displayed both P53 mutation and allele loss (Du et al, 1995).…”

Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation

“…Whilst structural alterations of p53 are very rare in the chronic phase of CML, they are detected in 25 ± 30% of CML blast crisis cases (Ahuja et al, 1989;Mashal et al, 1990;Prokocimer and Rotter, 1994). Although the majority of studies concentrate on p53 mutations, several reports have implicated a mere reduction in wild type (wt) p53 gene dosage as a factor of key importance for the development of the accelerated phase Nakai et al, 1992;Rovira et al, 1995). reported that the loss of a wtp53 allele preceded any p53 mutation and that the hemizygous wtp53 expression conferred a growth advantage on the cells.…”