Assessment of the key role of TP53 dysfunction in CLL drug-resistant patients
The TP53 abnormalities are, today, the only genetic alteration requiring a specific therapy. Given this clinical relevance, our team has recently developed an efficient and reliable p53 functional assay fully validated in a clinical prospective. Thus, each CLL patient from GHPS is now screened by three “TP53 approaches”: del17p by FISH, TP53 mutations by NGS, and p53 protein function by our test. This broad exploration has uncovered a representative population of discordant CLLs who presents dysfunctionality in the p53 PCD pathway without disruption in the TP53 gene. Thus, we plan to analyze in detail whether this discrepancy is predictive of drug-resistance (flow cytometry in vitro assessments). A complementary NGS approach will allow us to search for genetic alterations in the members of the p53-pathway, including p21. A key alternative application of our p53 functional assay will be to test its efficiency in the assessment of lesser-known TP53 mutations associated to drug resistance (in collaboration with Dr. Soussi, CR Cordeliers, the FILO group, E. Verhoeyen and F.L. Cosset, ENS Lyon). We plan to apply our test in a cohort of 340 CLLs containing 450 different TP53 mutations. A comparison of functional data may help to determine the prognostic and drug resistance impact of each mutation.