TRAIL mediates and sustains constitutive NF-κB activation in LGL leukemia

Abstract

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.

Vitamin D pathway activation selectively deactivates signal transducer and activator of transcription (STAT) proteins and inflammatory cytokine production in natural killer leukemic large granular lymphocytes

“…From the overlapping cytokines, we found some potential biomarkers to pursue. Several studies found IL-6 and/or TRAIL were elevated in TLGLL serum/plasma samples [40, 50, 51, 54], which we also observed in the NK-LGLL patients in this study. Interestingly, all three T-LGLL studies showed IL-8 was significantly elevated in T-LGLL compared to normal donors.…”

“…G-CSF/CSF-3 and GM-CSF are colony stimulating factors that typically target stem cells in the bone marrow for the purpose of granulocyte production [11]. TRAIL, which our lab has found to be elevated in LGLL [51], is a tumor necrosis family ligand that typically induces apoptosis through a death receptor [52]. Epidermal growth factor (EGF) can signal through STAT5 in trophoblastic cell lines [53], but its potential role in leukemia is currently unclear.…”

Bone Marrow Failure Syndromes, Overlapping Diseases with a Common Cytokine Signature

“…Apoptotic inhibition is also mediated by increased activation of the PI3K/Akt signaling pathway via RANTES, IL-18, and MIP-1b at higher serum concentrations in LGL patients compared with healthy subjects [ 101 , 102 ]. Moreover, hyperactivation of NF-κB through TRAIL receptor activation can also lead to increased resistance to apoptosis in LGLs [ 103 ]. In addition, circulating levels of IFN-α2, IFN-γ, monocyte chemoattractant protein-1, epidermal growth factor, IL-6, IL-8, IL-10, IL-1β, IL-12p35, IL-1Ra, and MIP1-a are increased in the sera of LGL leukemia patients ( Table 3 ) [ 104 , 105 ].…”

An Analytically and Diagnostically Sensitive RNA Extraction and RT-qPCR Protocol for Peripheral Blood Mononuclear Cells

“…RNA-based assays enable analysis of basal expression profiles and responses to antigen or mitogen stimulation (3,4). Human PBMCs are a common source of RNA as collection of blood is less invasive and allows in-depth monitoring of many aspects of immunobiology (1,5) including identification, classification and prognosis of cancers (6)(7)(8)(9)(10)(11) monitoring inflammation (12,13), and evaluating therapeutic efficacy (14)(15)(16)(17).…”