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

Abbreviations

TNF-α
Tumor necrosis factor alpha
TGF-β
Transforming growth factor beta
IL-1β
Interleukin-1 beta
bFGF
Basic fibroblast growth factor
VEGF
Vascular endothelial growth factor
IL-6
Interleukin-6
Bcl-2
B-cell lymphoma 2
Bcl-xL
B-cell lymphoma-extra large
Mcl-1
Myeloid cell leukemia 1
Bax
Bcl-2-associated X
Bak
Bcl-2 homologous antagonist killer
Bid
BH3 interacting-domain death agonist
Bcl-xS
B-cell lymphoma-extra short
Bad
Bcl-2-associated death promoter
Bik
Bcl-2-interacting killer
Puma
p53 upregulated modulator of apoptosis
Noxa
Phorbol-12-myristate-13-acetate-induced protein 1
Hrk
Activator of apoptosis harakiri