Apoptosis is avoided by myeloma cells through a number of mechanisms. High proteasome activity prevents the unfolded protein response from activating apoptosis.22,25 Interactions with the bone marrow stromal cells induce the secretion of cytokines and growth factors. These interactions lead to the activation of NF-kB and Notch-1, as well as the secretion of soluble factors such as TNF-α, TGF-β, IL-1β, bFGF, VEGF, and IL-6. Together these signals favor myeloma cell survival by shifting the balance toward anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1, and away from pro-apoptotic factors Bax, Bak, Bid, Bcl-xS, Bad, Bik, Puma, Noxa, and Hrk.25,26
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