Although mutations in BTK and, less frequently, PLCG2 signaling downstream of BTK have been identified as responsible for resistance to BTK inhibitors [33] in some lymphoma cases, this mutational mechanism is rarely observed in MCL, indicating that other mechanisms, such as cell reprogramming [34], apparently involving metabolic rewiring from reliance on glycolysis to mitochondrial respiration (Fig. 3a) [35], are responsible for MCL resistance to BTK inhibition. This evidence concerns the gene PLCG2 and mantle cell lymphoma.