14 research outputs found
STAT3 dysregulation in mature T and NK cell lymphomas
T cell lymphomas comprise a distinct class of non-Hodgkin’s lymphomas, which include mature T and natural killer (NK) cell neoplasms. While each malignancy within this group is characterized by unique clinicopathologic features, dysregulation in the Janus tyrosine family of kinases/Signal transducer and activator of transcription (JAK/STAT) signaling pathway, specifically aberrant STAT3 activation, is a common feature among these lymphomas. The mechanisms driving dysregulation vary among T cell lymphoma subtypes and include activating mutations in upstream kinases or STAT3 itself, formation of oncogenic kinases which drive STAT3 activation, loss of negative regulators of STAT3, and the induction of a pro-tumorigenic inflammatory microenvironment. Constitutive STAT3 activation has been associated with the expression of targets able to increase pro-survival signals and provide malignant fitness. Patients with dysregulated STAT3 signaling tend to have inferior clinical outcomes, which underscores the importance of STAT3 signaling in malignant progression. Targeting of STAT3 has shown promising results in pre-clinical studies in T cell lymphoma lines, ex-vivo primary malignant patient cells, and in mouse models of disease. However, targeting this pleotropic pathway in patients has proven difficult. Here we review the recent contributions to our understanding of the role of STAT3 in T cell lymphomagenesis, mechanisms driving STAT3 activation in T cell lymphomas, and current efforts at targeting STAT3 signaling in T cell malignancies
Current Status and Future Directions in Graft-Versus-Host Disease Prevention Following Allogeneic Blood and Marrow Transplantation in Adults
Graft-versus-host disease (GvHD) in its acute and chronic forms continues to represent a significant barrier to the success and wide-applicability of blood and marrow transplantation as a potentially curative treatment modality for a number of benign and malignant blood conditions. Presently, calcineurin inhibitor (CNI)-based regimens remain the most commonly used prevention strategy, although post-transplant cyclophosphamide is emerging as an alternative approach, and is providing a backbone for innovative CNI-free combinations. In this paper, we review the current strategies used for the prevention of GvHD, and highlight some of the developing and promising combinations
Role of SIRT1 in autoimmune demyelination and neurodegeneration
Abstract Multiple sclerosis (MS) is a demyelinating disease characterized by chronic inflammation of the central nervous system, in which many factors can act together to influence disease susceptibility and progression. SIRT1 is a member of the histone deacetylase class III family of proteins and is an NAD ? -dependent histone and protein deacetylase. SIRT1 can induce chromatin silencing through the deacetylation of histones and plays an important role as a key regulator of a wide variety of cellular and physiological processes including DNA damage, cell survival, metabolism, aging, and neurodegeneration. It has gained a lot of attention recently because many studies in animal models of demyelinating and neurodegenerative diseases have shown that SIRT1 induction can ameliorate the course of the disease. SIRT1 expression was found to be decreased in the peripheral blood mononuclear cells of MS patients during relapses. SIRT1 represents a possible biomarker of relapses and a potential new target for therapeutic intervention in MS. Modulation of SIRT1 may be a valuable strategy for treating or preventing MS and neurodegenerative central nervous system disorders
Recommended from our members
miR-29 Sustains B Cell Survival and Controls Terminal Differentiation via Regulation of PI3K Signaling
The phosphatidylinositol 3-kinase (PI3K) signaling cascade downstream of the B cell receptor (BCR) signalosome is essential for B cell maturation. Proper signaling strength is maintained through the PI3K negative regulator phosphatase and tensin homolog (PTEN). Although a role for microRNA (miRNA)-dependent control of the PTEN-PI3K axis has been described, the contribution of individual miRNAs to the regulation of this crucial signaling modality in mature B lymphocytes remains to be elucidated. Our analyses reveal that ablation of miR-29 specifically in B lymphocytes results in an increase in PTEN expression and dampening of the PI3K pathway in mature B cells. This dysregulation has a profound impact on the survival of B lymphocytes and results in increased class switch recombination and decreased plasma cell differentiation. Furthermore, we demonstrate that ablation of one copy of Pten is sufficient to ameliorate the phenotypes associated with miR-29 loss. Our data suggest a critical role for the miR-29-PTEN-PI3K regulatory axis in mature B lymphocytes