Here the authors generate mouse models of Tp53- and Atm-defective CLL mimicking the high-risk form of human disease and show that Atm-deficient CLL is sensitive to PARP1 inhibition.
MYD88-mutated CLL formed a prognostically favorable subset with a high frequency of del(13q), mutated IGHV status and no adverse aberrations (del(11q), del(17p), TP53 mutations).
TP53 mutation was present in 81% of del(17p) CLL, mostly clonal (82%), and clonal mutations with del(17p) exhibit shorter overall survival than subclonal mutations with del(17p) (P = 0.019).
TP53 mutations predominate in IG-unmutated CLL, whereas the opposite is seen for MYD88 mutations, enriched in IG-mutated CLL) and in subsets of cases with stereotyped IG (enrichment for SF3B1 mutations in CLL subset #2).
In this randomised, double-blind, phase 3 study (CLLM1; CLL Maintenance 1 of the German CLL Study Group), patients older than 18 years and diagnosed with immunophenotypically confirmed chronic lymphocytic leukaemia with active disease, who responded to chemoimmunotherapy 2-5 months after completion of first-line therapy and who were assessed as having a high risk for an early progression with at least a partial response after four or more cycles of first-line chemoimmunotherapy, were eligible if they had high minimal residual disease levels or intermediate levels combined with an unmutated IGHV gene status or TP53 alterations.
Our data suggest that some TP53 variants may affect the risk of CLL. rs1800372 polymorphism might be the marker of unfavorable prognosis of the disease.
These agents co-induce p53 and NF-κB-dependent gene expression in cell lines from breast and colon cancer and in primary chronic lymphatic leukemia (CLL) cells.
Telomere shortening, TP53 mutations and deletions in chronic lymphocytic leukemia result in increased chromosomal instability and breakpoint clustering in heterochromatic regions.
We found that any type of TP53 alteration was associated with very short telomeres and high hTERT expression, independently of other biological CLL features.
It is hoped that NGS will not only contribute to a better understanding of chronic lymphocytic leukaemia (CLL), but will identify disease subsets that could benefit from specific treatment interventions.Recent advances in diagnosis (e.g. high-resolution immunophenotyping, markers of genetic abnormalities), prognosis (e.g. biomarkers), response predictors [e.g. del(17p)/TP53 mutations even at subclonal level], treatment (e.g.
CD49d, the alpha-chain of the integrin heterodimer α4β1, was identified among the strongest predictors of overall survival (OS) in chronic lymphocytic leukemia (CLL), along with IGHV mutational status and deletion of the 17p chromosome involving TP53.
Loss of p53 function in CLL cells due to chromosome 17p deletion or p53 mutations often leads to a more malignant disease phenotype and is associated with drug resistance and poor clinical outcome.
Quantitative analyses of clonal dynamics uncover rising, stable, and falling clones and subclones without clear evidence that gene mutations other than in TP53 and possibly SAMHD1 are frequently selected for at CLL relapse.