Here, we demonstrate the transcriptional activity of EVI1 is dependent on activation of lymphoid enhancer-binding factor 1 (LEF1)/β-catenin complex by BCR-ABL with loss of p53 function during CML-BC.
Two functional single nucleotide polymorphisms (SNPs), p53R72P and MDM2 SNP309, are associated with alternation of p53 activity, however the association regarding CML susceptibility and BP transformation under imatinib treatment is unclear.
Selected candidate genes mapping within the aberrant genomic regions were sequenced and mutation of the TP53 gene was observed in one case in BC and of the ASXL1 gene in 6 of 41 cases in CP or BC.
However, one patient, who had a p53 point mutation, showed a massive elevation of p53 mRNA during blast crisis yet, conversely, a considerable reduction in Apaf-1 mRNA and Fas mRNA.
In order to ascertain whether p53 has a role in chronic myeloid leukemia hematopoietic progenitor response to the innovative tyrosine kinase inhibitor STI571 (Imatinib), we overexpressed a wild type (wt) p53 construct in the K562 cell line, generated from a human blast crisis and lacking endogenous p53.
Apart from the strong phenotypic impact of addition of acute myeloid leukemia/myelodysplasia-associated translocations and inversions, such as inv(3)(q21q26), t(3;21)(q26;q22), and t(15;17)(q22;q12-21), in CML BC, only a few significant differences between myeloid and lymphoid BC are discerned, with i(17q) and TP53 mutations being more common in myeloid BC and monosomy 7, hypodiploidy, and CDKN2A deletions being more frequent in lymphoid BC.
Our study presents in vivo evidence that acquired loss of p53 contributes to the blastic transformation of p210(bcr/abl)-expressing hematopoietic cells and provides insights into the molecular mechanism for blast crisis of human CML.(Blood.2000;95:1144-1150)
Since mutation and/or deletion of the p53 gene has been reported to be associated with disease progression in a wide variety of human cancers, including adult-type chronic myelogenous leukaemia, we studied the p53 gene in 20 patients with JMML (16 samples in chronic phase and seven at blast crisis).
Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations.
We found a marked decrease in Rb gene product and rearrangements of the p53 gene simultaneously in two cases of biphenotypic blast crisis of CML (myeloid and B-lymphoid).
To test whether the functional loss of p53 plays a direct role in the transition of chronic phase to blast crisis, bone marrow cells from p53+/+ or p53-/- mice were infected with a retrovirus carrying either the wild-type BCR/ABL or the inactive kinase-deficient mutant, and were assessed for colony-forming ability.
These data indicate that: a) P53 gene mutations occur in a significant but not a large number of CML acute phase cases; b) P53 gene point mutations seem to correlate strongly with the infrequent extramedullary presentation of the blast crisis; c) the presence of the same P53 gene point mutation in extramedullary and bone marrow blast cells confirms the common clonal origin of the two cellular populations.
A concomitant search for a possible involvement of the p53 tumour suppressor gene in the same series of patients showed mutations of the gene and loss of heterozygosity at 17p only in myeloid blast crisis, suggesting the presence of distinct molecular pathways in the pathogenesis of lymphoid and myeloid blast crisis.
During the past several years, accumulated evidence suggests that changes in the p53 gene are commonly associated with blast crisis of chronic myeloid leukemia (CML) but rarely with chronic phase, and they are represented by rearrangements, deletions and point mutations.
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.
Our results suggest that, in some cases, sequential investigations through CML disease progression of p53 mutations and other oncogenes/proto-oncogenes may provide early indications of the routes of disease progression to blast crisis.
Multiple aberrant splicing of the p53 transcript without genomic mutations around exon-intron junctions in a case of chronic myelogenous leukaemia in blast crisis: a possible novel mechanism of p53 inactivation.