Multiple myeloma is an incurable malignancy mainly due to the emergence of drug resistance. Mechanistic studies have shown that the expression of MDR1/P-glycoprotein accounts for only a portion of the drug resistant phenotype. Another mechanism of drug resistance in this disease may be the inability of anticancer drugs to activate signaling pathways required for programmed cell death (PCD). The PCD pathways may be tissue or tumor specific, and anti-cancer drugs may be more effective at activating certain pathways compared to others. The Fas/Fas Ligand pathway serves primarily as a means to regulate the homeostasis of the immune system by eliminating chronically activated lymphocytes. If anti-cancer drugs initiate PCD in hematopoietic malignancies by utilizing components of the Fas-mediated apoptotic pathway, then an abnormality or blockade in this pathway could result in drug resistance. Conversely, if anti-cancer drugs select for an abnormality or mutation in the Fas pathway, then this could result in resistance to Fas-mediated apoptosis. The applicant will examine the signaling pathway for Fas-mediated apoptosis in myeloma cell lines and patient specimens to determine if a relationship exists between drug sensitivity and Fas-mediated apoptosis.
Specific Aims 1 and 2 will focus on the Fas receptor (Fas) and Fas ligand (FasL) by determining if loss of expression or presence of mutations in either of these molecules impairs Fas-mediated or drug induced apoptosis.
Specific Aim 3 will examine the role of IL-6 in preventing PCD mediated by Fas activation or drug exposure.
Specific Aim 4 will determine if drug treatment selects for Fas-mediated resistance in vivo. A fundamental understanding of Fas-mediated apoptosis, and mechanisms by which cells become resistant to this apoptotic pathway, may be critical to the understanding of how myeloma cells avoid immune surveillance and possibly become drug resistant.
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