B-chronic lymphocytic leukemia (B-CLL) patients harboring p53 mutations are invariably refractory to therapies based on purine analogues and have limited treatment options and poor survival.
While efficacy of high-dose corticosteroids is excellent including responses in patients with bulky lymphadenopathy or those considered ultra high-risk CLL because of deletion and/or mutation of p53 gene, the duration of response is still unsatisfactory.
Because inactivation of p53 by deletion and/or mutations also impacts on the clinical course of B-cell chronic lymphocytic leukemia (B-CLL), we assessed the role of the SNP309 genotype in B-CLL.
Wild and mutant forms of p53 protein were evaluated in 197 B-CLL patients at diagnosis or before progression by an immunoenzymatic method in plasma using an anti-p53 monoclonal antibody.
Although NOTCH1 mutated patients were devoid of TP53 disruption in more than 90% cases in both training and validation series, the OS predicted by NOTCH1 mutations was similar to that of TP53 mutated/deleted CLL.
The different types of drug resistance encountered in chronic lymphocytic leukemia (CLL) cannot be fully accounted for by the 17p deletion (and/or TP53 mutation), a complex karyotype (CK), immunoglobulin heavy-chain variable region genes (IGHV) status and gene mutations.
Here, we present two distinct methodologies which can be used to identify TP53 mutations in CLL patients; both protocols are primarily intended for research purposes.
Between Oct 23, 2014, and April 23, 2018, 85 patients with chronic lymphocytic leukaemia were enrolled. del(17p) was detected in four (5%) of 83 patients and TP53 mutations were noted in three (4%) of 81 patients; two patients had both del(17p) and TP53 mutations.
Simultaneous detection of BCL-2 protein, trisomy 12, retinoblastoma and P53 monoallelic gene deletions in B-cell chronic lymphocytic leukemia by fluorescence in situ hybridization (FISH): relation to disease status.
Inhibitors of heat-shockprotein 90 (Hsp90) have been proposed as a novel therapeutic option for Chronic Lymphocytic Leukaemia (CLL), particularly as their mechanism of action appears independent of mutations of ATM or TP53.
Excepting NOTCH1, TP53 and XPO1, which showed a lower incidence in MBL, genes were mutated with a similar prevalence to CLL, indicating the early origin of most driver mutations in the MBL/CLL continuum.
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.
Patients with treatment indications should be investigated for TP53 mutations in addition to the work-up recommended by the International workshop on CLL guidelines.
Our data provide evidence that 17p loss may play an additional pathogenetic role in B-CLL and suggest that the concomitant loss of multiple tumor suppressor genes could be responsible for the highly adverse prognostic relevance associated with TP53 loss.
Assessment of somatic and germline TP53 alterations has now reached the clinic and is required in several circumstances such as the identification of the most effective cancer therapy for patients with chronic lymphocytic leukemia (CLL).