Histone Deacetylase 6 (HDAC6) As A Therapeutic Target in Chronic Lymphocytic Leukemia
Poster Dec 13, 2017
Kamira K. Maharaj, John Powers, Susan L. Deng, Alex Achille, Mibel Pabon-Saldana, Renee Fonseca, Steven N. Quayle, Simon S. Jones, Eva Sahakian and Javier Pinilla-Ibarz
Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the western world and is characterized by an accumulation of CD5+ B cells in circulation and lymphoid tissue. There is a need to identify novel therapies for CLL patients due to prevalence of partial responses and relapsed/refractory disease. In CLL, an immunosuppressive phenotype enables the malignant B cell to evade immune detection, leading to immune suppression. In recent years, epigenetic changes prompted by proteins known as histone deacetylases (HDACs) have gained special attention predominantly because of their active role in the regulation of pathogenesis and immune-related pathways in CLL; though the precise mechanism by which these regulatory events take place has yet to be elucidated. In addition to the well-recognized role of histone deacetylase inhibitors (HDACi) in the control of cell cycle and apoptosis, HDACi have a potential role in modulating the immunobiology of CLL. HDACs may therefore represent viable targets to develop new immunomodulating therapies for CLL.
In this study, we aimed to investigate the role of histone deacetylase 6 (HDAC6) in immunobiology of CLL and determine how HDAC6 may regulate malignant B cell survival pathways. Further, we aimed to determine efficacy of HDAC6 inhibition in a CLL murine model.
Collectively our data confirms the importance of HDAC6 to CLL progression. We have found that HDAC6 inhibition regulates CLL immunobiology to deter tumor cell immune evasion mechanisms and reinvigorate a beneficial immune response against CLL disease. Results from our preclinical CLL models suggest that HDAC6 represents a viable therapeutic target in CLL. This target may be developed with the intention to treat relapsed/refractory CLL patients or weaker, aged patients.
Genome-wide association studies (GWAS) have identified more than 100 genetic loci associated with type 2 diabetes. The majority of these are located in the intergenic or intragenic regions suggesting that the implicated variants may alter chromatin conformation. This, in turn, is likely to influence the expression of nearby or more remotely located genes to alter beta cell function. At present, however, detailed molecular and functional analyses are still lacking for most of these variants. We recently analysed one of these loci and mapped five causal variants in an islet-specific enhancer cluster within the STARD10 gene locus. Here, we aimed to understand how these causal variants influence b-cell function by alteration of the chromatin structure of enhancer clusterREAD MORE
The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of phase I (cytochrome P450s), phase II metabolizing enzymes and transporter genes in response to xenobiotics, including prescription drugs.READ MORE
Early life stress (ELS) is highly associated with development of psychopathology
and mood disorders in adulthood. Genetic studies have identified variation in the gene calcium voltage-gated channel subunit alpha1C (CACNA1C) to increase risk for several psychiatric disorders. This poster assessed the expression of Cacna1c following prepubertal stress.