Translation-coupled mRNA quality control mechanisms.

mRNA surveillance pathways are essential for accurate gene expression and to maintain translation homeostasis, ensuring the production of fully functional proteins. Future insights into mRNA quality control pathways will enable us to understand how cellular mRNA levels are controlled, how defective or unwanted mRNAs can be eliminated, and how dysregulation of these can contribute to human disease. Here we review translation-coupled mRNA quality control mechanisms, including the non-stop and no-go mRNA decay pathways, describing their mechanisms, shared trans-acting factors, and differences. We also describe advances in our understanding of the nonsense-mediated mRNA decay (NMD) pathway, highlighting recent mechanistic findings, the discovery of novel factors, as well as the role of NMD in cellular physiology and its impact on human disease.

A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival.

Epigenomic dysregulation is a common pathological feature in human hematological malignancies. H3K9me3 emerges as an important epigenomic marker in acute myeloid leukemia (AML). Its associated methyltransferases, such as SETDB1, suppress AML leukemogenesis, whilst H3K9me3 demethylases KDM4C is required for mixed-lineage leukemia rearranged AML. However, the specific role and molecular mechanism of action of another member of the KDM4 family, KDM4A has not previously been clearly defined. In this study, we delineated and functionally validated the epigenomic network regulated by KDM4A. We show that selective loss of KDM4A is sufficient to induce apoptosis in a broad spectrum of human AML cells. This detrimental phenotype results from a global accumulation of H3K9me3 and H3K27me3 at KDM4A targeted genomic loci thereby causing downregulation of a KDM4A-PAF1 controlled transcriptional program essential for leukemogenesis, distinct from that of KDM4C. From this regulatory network, we further extracted a KDM4A-9 gene signature enriched with leukemia stem cell activity; the KDM4A-9 score alone or in combination with the known LSC17 score, effectively stratifies high-risk AML patients. Together, these results establish the essential and unique role of KDM4A for AML self-renewal and survival, supporting further investigation of KDM4A and its targets as a potential therapeutic vulnerability in AML.

The Emerging Role of H3K9me3 as a Potential Therapeutic Target in Acute Myeloid Leukemia.

Growing evidence has demonstrated that epigenetic dysregulation is a common pathological feature in human cancer cells. Global alterations in the epigenetic landscape are prevalent in malignant cells across different solid tumors including, prostate cancer, non-small-cell lung cancer, renal cell carcinoma, and in haemopoietic malignancy. In particular, DNA hypomethylation and histone hypoacetylation have been observed in acute myeloid leukemia (AML) patient blasts, with histone methylation being an emerging area of study. Histone 3 lysine 9 trimethylation (H3K9me3) is a post-translational modification known to be involved in the regulation of a broad range of biological processes, including the formation of transcriptionally silent heterochromatin. Following the observation of its aberrant methylation status in hematological malignancy and several other cancer phenotypes, recent studies have associated H3K9me3 levels with patient outcome and highlighted key molecular mechanisms linking H3K9me3 profile with AML etiology in a number of large-scale meta-analysis. Consequently, the development and application of small molecule inhibitors which target the histone methyltransferases or demethylase enzymes known to participate in the oncogenic regulation of H3K9me3 in AML represents an advancing area of ongoing study. Here, we provide a comprehensive review on how this particular epigenetic mark is regulated within cells and its emerging role as a potential therapeutic target in AML, along with an update on the current research into advancing the generation of more potent and selective inhibitors against known H3K9 methyltransferases and demethylases.

Patient Disposition and Clinical Outcome After Referral to a Dedicated TAVI Clinic.

Introduction: Transcatheter aortic valve implantation (TAVI) is the standard of care for the majority of patients with severe symptomatic aortic stenosis (AS) at excessive-, high- and intermediate-surgical risk. A proportion of patients referred for TAVI do not undergo the procedure and proceed with an alternate treatment strategy. There is scarce data describing the final treatment allocation of such patients. Hence, we sought to evaluate the final treatment allocation of patients referred for TAVI in contemporary practice. Methods: We performed a single center prospective observational study, including all patients referred to our institution for treatment of severe aortic stenosis between February 2014 and August 2017. Baseline demographic and clinical data were recorded. Patients were categorized according to treatment allocation: TAVI, surgical aortic valve replacement (SAVR) or optimal medical therapy (OMT). Clinical outcomes were adjudicated according to VARC-2 definitions. All patients were discussed at a dedicated Heart Team meeting. Results: Total of 245 patients were referred for assessment to a dedicated TAVI clinic during the study period. Patients with moderate (N = 32; 13.1%) and asymptomatic (N = 31; 13.1%) AS were excluded. Subsequently, 53.9% (N = 132) received TAVI, 12.7% (N =31) were managed with OMT, and 7.3% (N =18) had SAVR. Reasons for OMT included primarily: patient's preference (N = 12; 38.7%); excessive surgical risk (N = 4; 12.9%) and severe frailty (N = 5; 16.1%). Reasons for surgical referral included low surgical risk (N = 11; 61.1%), excessive annulus size (N = 5; 27.8%), and aortic root dilatation (N = 2; 11.1%). Patients proceeding to SAVR had lower surgical risk than those in either the OMT or TAVI cohorts (P < 0.001). Mean STS score in SAVR group was 2.2 ± 1.3 vs. 4.5 ± 2.4 in OMT cohort and 6.1 ± 4.9 in TAVI cohort. Six-month all-cause mortality was 16.7, 19.4, and 9.3% among those receiving SAVR, OMT, and TAVI, respectively. Conclusions: Almost half of all patients with severe AS referred to a dedicated TAVI clinic did not receive a TAVI. A considerable proportion of patients were reclassified as moderate AS (13%), were asymptomatic (13%), or intervention was determined to be futile (13%) due to advanced frailty. Early detection and increased awareness of valvular heart disease are required to increase the number of patients that can benefit from TAVI.

A molecular signature for delayed graft function.

Chronic kidney disease and associated comorbidities (diabetes, cardiovascular diseases) manifest with an accelerated ageing phenotype, leading ultimately to organ failure and renal replacement therapy. This process can be modulated by epigenetic and environmental factors which promote loss of physiological function and resilience to stress earlier, linking biological age with adverse outcomes post-transplantation including delayed graft function (DGF). The molecular features underpinning this have yet to be fully elucidated. We have determined a molecular signature for loss of resilience and impaired physiological function, via a synchronous genome, transcriptome and proteome snapshot, using human renal allografts as a source of healthy tissue as an in vivo model of ageing in humans. This comprises 42 specific transcripts, related through IFNγ signalling, which in allografts displaying clinically impaired physiological function (DGF) exhibited a greater magnitude of change in transcriptional amplitude and elevated expression of noncoding RNAs and pseudogenes, consistent with increased allostatic load. This was accompanied by increased DNA methylation within the promoter and intragenic regions of the DGF panel in preperfusion allografts with immediate graft function. Pathway analysis indicated that an inability to sufficiently resolve inflammatory responses was enabled by decreased resilience to stress and resulted in impaired physiological function in biologically older allografts. Cross-comparison with publically available data sets for renal pathologies identified significant transcriptional commonality for over 20 DGF transcripts. Our data are clinically relevant and important, as they provide a clear molecular signature for the burden of "wear and tear" within the kidney and thus age-related physiological capability and resilience.