Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia

BackgroundAcute leukemia is an epigenetically heterogeneous disease. The intensity of treatment is currently guided by cytogenetic and molecular genetic risk classifications; however these incompletely predict outcomes, requiring additional information for more accurate outcome predictions. We aimed to identify potential prognostic implications of epigenetic modification of histone proteins, with a focus on H3K4 and H3K27 methylation marks in relation to mutations in chromatin, splicing and transcriptional regulators in adult-onset acute lymphoblastic and myeloid leukemia.ResultsHistone 3 lysine 4 di- and trimethylation (H3K4me2, H3K4me3) and lysine 27 trimethylation (H3K27me3) mark expression was evaluated in 241 acute myeloid leukemia (AML), 114 B-cell acute lymphoblastic leukemia (B-ALL) and 14T-cell ALL (T-ALL) patient samples at time of diagnosis using reverse phase protein array. Expression levels of the marks were significantly lower in AML than in B and T-ALL in both bone marrow and peripheral blood, as well as compared to normal CD34+ cells. In AML, greater loss of H3K27me3 was associated with increased proliferative potential and shorter overall survival in the whole patient population, as well as in subsets with DNA methylation mutations. To study the prognostic impact of H3K27me3 in the context of cytogenetic aberrations and mutations, multivariate analysis was performed and identified lower H3K27me3 level as an independent unfavorable prognostic factor in all, as well as in TP53 mutated patients. AML with decreased H3K27me3 demonstrated an upregulated anti-apoptotic phenotype. In ALL, the relative quantity of histone methylation expression correlated with response to tyrosine kinase inhibitor in patients who carried the Philadelphia cytogenetic aberration and prior smoking behavior.ConclusionThis study shows that proteomic profiling of epigenetic modifications has clinical implications in acute leukemia and supports the idea that epigenetic patterns contribute to a more accurate picture of the leukemic state that complements cytogenetic and molecular genetic subgrouping. A combination of these variables may offer more accurate outcome prediction and we suggest that histone methylation mark measurement at time of diagnosis might be a suitable method to improve patient outcome prediction and subsequent treatment intensity stratification in selected subgroups

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

PONE-D-19-30554 Data Set

Minimal Data Set for manuscript PONE-D-19-30554 in PLOS ON

Neuroophthalmic Complications of Chemotherapy

Patients with cancer not infrequently develop neurologic or ophthalmologic conditions.curriculum_fellow; GVSchemotherapy; VBtreatmentofbraintumors; KBDneuroophthalmiccomplicationsofchemotherap

Introduction and Lessons from Vigabatrin (abstract)

It is often difficult to determine the validity of reported toxicity attributed to a drug and a neuro-ophthalmic abnormality. In some cases, the patient has received combination therapy, such as surgical resection and medical therapy, and in other cases, the complications are not the focus of the report. Some manuscripts consist of individual anecdotal case reports; in others, the evaluation or at least the description of findings is incomplete. Furthermore, the source of the reports in these patients may be varied, including from literature focused on genetics, neurosurgery, neurology, and ophthalmology.PBLI, Medical Knowledge, Patient Care, SBP, Professionalism, IPC

Introduction and Lessons from Vigabatrin (video)

Vigabatrin was introduced as an anti-seizure medication in the United Kingdom in 1989 and was extensively used until 1997 when concerns for peripheral visual field defects emerged. When the drug was approved in the United States in 2009 it carried a black box warning for the risk of permanent visual loss and the pharmaceutical company was mandated to create a drug registry to assess for visual deficits. The vigabatrin drug registry has documented a relatively large percentage (37%) of pre-existing, baseline visual deficits involving the visual system and a paucity (2%) of potential new visual findings. The vigabatrin vision study, a prospective, longitudinal, single-arm, open-label study, confirmed that adult patients with refractory complex partial seizures had a large number (around 33%) of visual deficits at baseline, and a single patient who developed bilateral peripheral field constriction about one year after therapy. An unexpected finding during this first year of therapy with vigabatrin was an increase in retinal thickness on optical coherence tomography. The experience from; vigabatrin in the United States emphasizes the importance of baseline eye findings when considering the potential for drug toxicity involving the visual pathways

Neuroophthalmic Complications of Chemotherapy

Patients with cancer not infrequently develop neurologic or ophthalmologic conditions.curriculum_fellow; GVSchemotherapy; VBtreatmentofbraintumors; KBDneuroophthalmiccomplicationsofchemotherap

An essential function of the SRC-3 coactivator in suppression of cytokine mRNA translation and inflammatory response

Steroid receptor coactivator-3 (SRC-3) is a transcriptional coactivator for nuclear receptors and other transcription factors. Although multiple physiological roles of SRC-3 have been revealed, its involvement in the inflammatory process remains unclear. Herein we show that SRC-3(-/-) mice are markedly hypersensitive to LPS-induced endotoxic shock. In response to LIPS, SRC-3(-/-) macrophages produce significantly more proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1 beta than wild-type controls, although they express similar amounts of cytokine mRNAs, suggesting that SRC-3 can exert effects at translational levels. Increased heavy polysome-associated TNF-alpha and IL-10 mRNAs in SRC-3(-/-) macrophages implicate SRC-3 as a translational repressor. SRC-3 may cooperate with other translational repressors such as TIA-1 and TIAR to regulate cytokine mRNA translation. Collectively, our studies reveal an essential function of SRC-3 as a coordinator of inflammatory mRNA translation and as a physiologic protective factor against the lethal endotoxic shock triggered by an acute inflammatory response