Dataset Information

TRAIL mediates and sustains constitutive NF-?B 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 ?B (NF-?B) is a central regulator of the survival network for leukemic LGL. However, the mechanisms that trigger constitutive activation of NF-?B 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-?B 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-?B 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-?B activation in leukemic LGL. Conversely, interruption of TRAIL-DcR2 signaling led to decreased NF-?B activation. Finally, a potential therapeutic application of proteasome inhibitors (bortezomib and ixazomib), which are known to inhibit NF-?B, was identified through their ability to decrease proliferation and increase apoptosis in LGL leukemia cell lines and primary patient cells.

SUBMITTER: Yang J

PROVIDER: S-EPMC6014359 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Yang Jun J LeBlanc Francis R FR Dighe Shubha A SA Hamele Cait E CE Olson Thomas L TL Feith David J DJ Loughran Thomas P TP

Blood 20180426 25

Large granular lymphocyte (LGL) leukemia results from clonal expansion of CD3<sup>+</sup> cytotoxic T lymphocytes or CD3<sup>-</sup> 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 sur ...[more]

PMID: 29699990

Similar Datasets

Project description:Pathologic conditions impair bone homeostasis. The transcription factor NF-κB regulates bone homeostasis and is central to bone pathologies. Whereas contribution of NF-κB to heightened osteoclast activity is well-documented, the mechanisms underlying NF-κB impact on chondrocytes and osteoblasts are scarce. In this study, we examined the effect of constitutively active IKK2 (IKK2ca) on chondrogenic and osteogenic differentiation. We show that retroviral IKK2ca but not GFP, IKK2WT, or the inactive IKK2 forms IKK2KM and IKK2SSAA, strongly suppressed osteogenesis and chondrogenesis, in vitro. In order to explore the effect of constitutive NF-κB activation on bone formation in vivo, we activated this pathway in a conditional fashion. Specifically, we crossed the R26StopIKK2ca mice with mice carrying the Col2-cre in order to express IKK2ca in osteoblasts and chondrocytes. Both chondrocytes and osteoblasts derived from Col2Cre/IKK2ca expressed IKK2ca. Mice were born alive yet died shortly thereafter. Histologically, newborn Col2Cre+/RosaIKK2ca heterozygotes (Cre+IKK2ca_w/f (het)) and homozygotes (Cre+IKK2ca_f/f (KI)) showed smaller skeleton, deformed vertebrate and reduced or missing digit ossification. The width of neural arches, as well as ossification in vertebral bodies of Cre+IKK2ca_w/f and Cre+IKK2ca_f/f, was reduced or diminished. H&E staining of proximal tibia from new born pups revealed that Cre+IKK2ca_f/f displayed disorganized hypertrophic zones within the smaller epiphysis. Micro-CT analysis indicated that 4-wk old Cre+IKK2ca_w/f has abnormal trabecular bone in proximal tibia compared to WT littermates. Mechanistically, ex-vivo experiments showed that expression of differentiation markers in calvarial osteoblasts derived from newborn IKK2ca knock-in mice was diminished compared to WT-derived cells. In situ hybridization studies demonstrated that the hypertrophic chondrocyte marker type-X collagen, the pre-hypertrophic chondrocyte markers Indian hedgehog and alkaline phosphatase, and the early markers Aggrecan and type-II collagen were reduced in Cre+IKK2ca_w/f and Cre+IKK2ca_f/f mice. Altogether, the in-vitro, in vivo and ex-vivo evidence suggest that IKK2ca perturbs osteoblast and chondrocyte maturation and impairs skeletal development.

Dataset Information

TRAIL mediates and sustains constitutive NF-?B activation in LGL leukemia.

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets