The aim of this study was twofold: 1) to characterize the MDR status of IGHV M and UM cells, by evaluating the activity of Ras/ERK1–2, RhoA/RhoA kinases, and HIF-1α/Pgp axis under basal conditions and after exposure to SCs; 2) to determine whether targeting the Mev pathway and its downstream signaling eventually restores the sensitivity of MDR+ CLL cells to Doxo. The gene discussed is RHOA; the disease is B-cell chronic lymphocytic leukemia.