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Research topics - Adaptation of chronic lymphocytic leukemia to ibrutinib

Adaptation of chronic lymphocytic leukemia to ibrutinib is mediated by epigenetic plasticity of residual disease and bypass signaling via MAPK pathway

Ibrutinib inhibits the BTK molecule downstream the B-cell receptor. Though highly active in chronic lympho- cytic leukemia, detectable minimal residual disease persists for years under ibrutinib until the development of resistance. The study aims at a multilayer characteriza- tion of the adaptation process that allows residual cells to persist despite BTK inhibition. The study has enrolled 33 patients treated with ibrutinib. Ibrutinib induces chroma- tin dynamics in the minimal residual disease, and maintains its chromatin in a predominantly closed state. The collected data indicate that the minimal residual disease persisting under ibrutinib adapts its phenotype, mainly in a non-genetic way, by maintaining functional competence of the MAPK pathway. The study provides the rationale for combining MAPK pathway inhibitors to BTK inhibitors.