Large granular lymphocyte (
LGL) leukemia results from clonal expansion of CD3+ cytotoxic T lymphocytes or CD3- natural killer (NK) cells. Chronic
antigen stimulation is postulated to promote long-term survival of
LGL leukemia cells through constitutive activation of multiple survival pathways, resulting in global dysregulation of apoptosis and resistance to activation-induced cell death. We reported previously that nuclear factor κB (NF-κB) is a central regulator of the survival network for leukemic LGL. However, the mechanisms that trigger constitutive activation of NF-κB in
LGL leukemia remain undefined.
Tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) is known to induce apoptosis in
tumor cells but can also activate NF-κB through interaction with
TRAIL receptors 1, 2, and 4 (also known as DR4, DR5, and DcR2, respectively). The role of TRAIL has not been studied in
LGL leukemia. In this study, we hypothesized that TRAIL interaction with DcR2 contributes to NF-κB activation in
LGL leukemia. We observed upregulated TRAIL
messenger RNA and
protein expression in
LGL leukemia cells with elevated levels of soluble
TRAIL protein in
LGL leukemia patient sera. We also found that DcR2 is the predominant TRAIL receptor in
LGL leukemia cells. We demonstrated that TRAIL-induced activation of DcR2 led to increased NF-κB activation in leukemic LGL. Conversely, interruption of TRAIL-DcR2 signaling led to decreased NF-κB activation. Finally, a potential therapeutic application of
proteasome inhibitors (
bortezomib and
ixazomib), which are known to inhibit NF-κB, was identified through their ability to decrease proliferation and increase apoptosis in
LGL leukemia cell lines and primary patient cells.