Several mechanisms can contribute to this resistance: clonal shifts with the expansion of clones with higher genomic instability and copy number alterations in genes such as NOTCH1, SF3B1, and TP53, point mutations occurring at the BH3-binding pocket of the BCL-2 protein, and increased dependence of the CLL cells on other anti-apoptotic pathway such as MCL-1. The gene discussed is NOTCH1; the disease is B-cell chronic lymphocytic leukemia.