In search of the molecular mechanism responsible for decreased PTEN expression, we have uniquely characterized a novel role for 14q32 cluster miRNAs-dependent regulation of the PTEN/AKT/mTOR axis in mediating resistance to BTK inhibition in CLL and DLBCL cells in the absence of BTK or PLCG2 mutations. Here, BTK is linked to B-cell chronic lymphocytic leukemia.