The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia
Figure 1
Molecular interactions in chemoresistance. Chemoresistant chronic myeloid leukemia (CML) cells display a multifactorial resistance phenotype characterized by deregulation of diverse signaling pathways which may act in concert or individually to prevent chemotherapy sensitivity (b). Resistant cells display constitutively active nuclear expression of NFκB which contributes to stimulate transcription of the inhibitor of apoptosis proteins (IAPs) survivin and XIAP and also the efflux drug transporter ABCB1. The transcription factor FoxO3a, which usually acts as an apoptosis mediator, may also lead to enhanced ABCB1 transcription when chronically activated. In addition, chemoresistant CML cells display an overexpression of the efflux pump ABCG2 and reduced levels of the influx drug transporter SLC22A1. By contrast, many chemotherapeutic agents may overcome resistance and sensitize cells to apoptosis by modulating these pathways (a). Drug-mediated down-regulation of NFκB, survivin, XIAP, and ABCB1 is associated with increased apoptotic levels, emphasizing their role as resistance factors. In addition, chemotherapy-induced FoxO3a activation results in cell cycle arrest and apoptosis by up-regulating BIM, P27/KIP1, and TRAIL and inhibiting CYCLIN D and ID1 genes.
