Unravelling the suboptimal response of TP53-mutated chronic lymphocytic leukaemia to ibrutinib.
Anna GuariniNadia PeragineMonica MessinaMarilisa MarinelliCaterina IlariLuciana CafforioSara RaponiSilvia BoninaPaola MarigliaFrancesca Romana MauroGianluca GaidanoIlaria Del GiudiceRobin FoàPublished in: British journal of haematology (2018)
TP53-disrupted chronic lymphocytic leukaemia (CLL) patients show a suboptimal long-term response to ibrutinib. We hereby report that ibrutinib-induced in vitro apoptosis and proliferation inhibition were significantly lower in TP53-mutated (TP53-M) CLL cells compared to TP53 wild-type cells. Contrariwise, venetoclax effectively killed TP53-M cells. Gene expression profile analysis of TP53-M cells revealed a downmodulation of B-cell receptor (BCR)-related genes and an upmodulation of genes with anti-apoptotic/pro-survival activity, suggesting that the survival and proliferation of TP53-M cells are less dependent on the BCR pathway. These observations further support the use of drug combinations for the optimal management of TP53-M CLL patients.
Keyphrases
- cell cycle arrest
- induced apoptosis
- cell death
- chronic lymphocytic leukemia
- endoplasmic reticulum stress
- signaling pathway
- oxidative stress
- ejection fraction
- newly diagnosed
- emergency department
- chronic kidney disease
- gene expression
- copy number
- drug induced
- patient reported outcomes
- diabetic rats
- resting state
- anti inflammatory