Abstract
BackgroundThe Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib provided a breakthrough in the treatment of chronic lymphocytic leukaemia (CLL), but cases of resistance are now emerging. Whilst resistance is commonly associated with mutations in BTK itself and the downstream signalling molecule PLCg2, this is not always the case. In a recent study, we have detected some epigenomic plasticity correlated with the dynamics of CLL cell response to ibrutinib. To understand the mechanisms mediating resistance in CLL, it is important to be able to determine whether the observed phenotypic changes are driven solely by resistance cues (e.g. clonal evolution, activation of signalling bypassing BTK inhibition), or if they could also be the consequence of unrelated events.MethodsTo answer to this question, we have monitored chromatin changes happening in response to ibrutinib from the start of treatment until relapse in CLL cells from both a patient carrying a previously identified BTK C481S mutation and from a relapsing patient, for whom none of the classical genetic lesions associated with ibrutinib relapse was detected.ResultsWe established that the epigenome and gene expression in CLL cells from patients on ibrutinib changes with time independently of disease progression and identified two patterns of chromatin alterations, which are independent of resistance mechanisms; one ibrutinib-dependent and the other related to quiescence. Furthermore, by defining the main characteristics of resistance-independent epigenomic plasticity and excluding them from the analysis, we identified candidate genes potentially mediating disease progression.ConclusionThis two-step strategy could fundamentally alter the understanding of resistance to treatment in CLL.
The assessment of minimal residual disease in chronic lymphocytic leukaemia: comparison of multi-colour flow cytometry and bone marrow trephine biopsy
