We have investigated the frequency of p53 mutations in B- and T-cell human lymphoid malignancies, including acute lymphoblastic leukemia, the major subtypes of non-Hodgkin lymphoma, and chronic lymphocytic leukemia. p53 exons 5-9 were studied by using genomic DNA from 197 primary tumors and 27 cell lines by single-strand conformation polymorphism analysis and by direct sequencing of PCR-amplified fragments.
These findings suggest that p53 mutations are relatively rare in B-cell CLL, and largely predominate or may even be restricted to patients with 17p monosomy (who constitute about 5% of all B-cell CLL patients in large published series).
Our findings indicate that p53 gene mutations in B-CLL are associated with a poor clinical outcome and may be a prognostic indicator for drug resistance.
Mutations or deletions of the P53 gene are found in 10 to 15% of patients with advanced CLL and correlate with resistance to treatment and poor survival.
Overall, our data indicate that: 1) contrary to previous reports, Bcl-1 and Bcl-2 rearrangements are not involved in CD5+ B-CLL pathogenesis and 2) p53 mutations are present in 10% of cases at all stages of the disease.
This spectrum of p53 mutations in B-CLL together with the high frequency of transversion mutations and DNA strand bias may implicate environmental carcinogens associated with p53 gene damage in some B-CLL patients.
Here, an interphase cytogenetic study was performed to analyze the incidence and prognostic significance of a p53 gene deletion in B-CLL and related disorders.
Some aggressive variants have been recognized with a blastic or large cell morphology, higher proliferative activity, and shorter survival. p53 gene mutations in lymphoid neoplasms have been detected mainly in high grade lymphomas and have been associated with tumor progression in follicular and small lymphocytic lymphomas.
We conclude that 1) FISH is a simple and sensitive technique for the detection of numerical and structural chromosome abnormalities; 2) Its application to uncultured samples obviates the alteration of results originated by the probable growth advantage of the normal or neoplastic cell population in vitro; 3) Trisomy 12 appears to define a B-CLL subgroup of atypical morphology; and 4) The p53 deletion is correlated with advanced stage of disease and resistance to treatment.
Our data suggest that the Bcl-2/Bax alpha ratio is important for the regulation of B-CLL cell survival, that p53 over-expression in progressive B-CLL is the result of post-transcriptional modifications and that a directed PKA activation may potentiate the cytolytic effect of glucocorticoids in vivo.
It is concluded that RS was cytogenetically related with B-CLL in this patient, suggesting the occurrence of a bona fide transformation and that the mutation of p53 exon 7, in association with the development of 17p deletion, possibly played a role in the development of RS.
To investigate the degree and nature of somatic mutations and the role of antigen (Ag) in the clonal selection and expansion of isotype-switched CLLs, and to determine whether specific oncogene or tumor suppressor gene mutations are associated with isotype-switched CLLs, we analyzed the expressed Ig VH gene, bcl-1 and bcl-2 proto-oncogene, and p53 tumor suppressor gene configurations of 3 IgA-, 1 IgG-, and 1 IgA/ IgG-expressing CLLs.
Using Western blot analysis, we examined the levels of Bcl-2, Bax, Bcl-X and p53 protein expression and determined whether the levels of these proteins correlated with in vitro drug resistance in CLL patients' lymphocyte samples.
On the other hand, the molecular basis of some of these diseases (eg, the overexpression of the Prad1/CCND1 gene in mantle-cell lymphomas, the relationship between bcl-2 and bax expression in chronic lymphocytic leukemia homeostasis, the role of p53 tumor suppressor gene mutations in chronic lymphocytic leukemia progression) are increasingly well known.
Mutations in P53 were identified in 25 of 237 tumors (10.5%), which included 1 of 45 small lymphocytic lymphomas (SLLs), 2 of 38 follicular small cleaved-cell lymphomas (FSCCs), 2 of 35 follicular mixed small cleaved-cell and large-cell lymphomas (FMxs), 1 of 4 follicular large-cell lymphomas (FLCs), 1 of 14 diffuse small cleaved-cell lymphomas (DSCCs), 2 of 17 diffuse mixed small- and large-cell lymphomas (DMxs), and 16 of 84 diffuse large-cell lymphomas (DLCCs); the difference between the histologic groups was significant (P < .01).
There was no clinical, or haematological difference or difference in survival between ras positive and ras negative patients with acute myeloid leukaemia (AML) in adults or children, but ras mutations carried a poorer prognosis in childhood acute lymphocytic leukaemia and an increased risk of leukaemia in MDS. p53 mutations predominated in lymphoid leukaemia and were several fold more frequent in leukaemia in relapse than in the de novo disease, were associated with loss of the normal p53 allele (monosomy 17) in > 50% of cases and carried a poor prognosis in AML, MDS and chronic lymphatic leukaemia and a 3.8-fold increase risk of death in T cell acute lymphocytic leukaemia.