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PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia.

ABSTRACT: Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for multiple malignancies. In this study, we investigated the role of PRMT5 in human acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 and a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. We then identified PRMT5 substrates using multiplexed quantitative proteomics and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5 and that loss of PRMT5 leads to changes in alternative splicing of multiple essential genes. Our study proposes a mechanism for the requirement of PRMT5 for leukemia cell survival and provides potential biomarkers for the treatment response to PRMT5 inhibitors.

SUBMITTER: Radzisheuskaya A

PROVIDER: S-EPMC6858565 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia.

Radzisheuskaya Aliaksandra A Shliaha Pavel V PV Grinev Vasily V Lorenzini Eugenia E Kovalchuk Sergey S Shlyueva Daria D Gorshkov Vladimir V Hendrickson Ronald C RC Jensen Ole N ON Helin Kristian K

Nature structural & molecular biology 20191014 11

Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for multiple malignancies. In this study, we investigated the role of PRMT5 in human acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 and a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. We then identified PRMT5 substrates using multiplexed quantita ...[more]

PMID: 31611688

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Project description:BackgroundCurrently the leading cause of global disability, clinical depression is a heterogeneous condition characterised by low mood, anhedonia and cognitive impairments. Its growing incidence among young people, often co-occurring with self-harm, is of particular concern. We recently reported very high rates of depression among first year university students in Northern Ireland, with over 25% meeting the clinical criteria, based on DSM IV. However, the causes of depression in such groups remain unclear, and diagnosis is hampered by a lack of biological markers. The aim of this exploratory study was to examine DNA methylation patterns in saliva samples from individuals with a history of depression and matched healthy controls.ResultsFrom our student subjects who showed evidence of a total lifetime major depressive event (MDE, n = 186) we identified a small but distinct subgroup (n = 30) with higher risk scores on the basis of co-occurrence of self-harm and attempted suicide. Factors conferring elevated risk included being female or non-heterosexual, and intrinsic factors such as emotional suppression and impulsiveness. Saliva samples were collected and a closely matched set of high-risk cases (n = 16) and healthy controls (n = 16) similar in age, gender and smoking status were compared. These showed substantial differences in DNA methylation marks across the genome, specifically in the late cornified envelope (LCE) gene cluster. Gene ontology analysis showed highly significant enrichment for immune response, and in particular genes associated with the inflammatory skin condition psoriasis, which we confirmed using a second bioinformatics approach. We then verified methylation gains at the LCE gene cluster at the epidermal differentiation complex and at MIR4520A/B in our cases in the laboratory, using pyrosequencing. Additionally, we found loss of methylation at the PSORSC13 locus on chromosome 6 by array and pyrosequencing, validating recent findings in brain tissue from people who had died by suicide. Finally, we could show that similar changes in immune gene methylation preceded the onset of depression in an independent cohort of adolescent females.ConclusionsOur data suggests an immune component to the aetiology of depression in at least a small subgroup of cases, consistent with the accumulating evidence supporting a relationship between inflammation and depression. Additionally, DNA methylation changes at key loci, detected in saliva, may represent a valuable tool for identifying at-risk subjects.

Project description:Acute myeloid leukemia (AML) is an infrequent disease, and it is associated with high morbidity and mortality. It harbors a unique configuration of cytogenetic abnormalities and molecular mutations that can be detected using microscopic and molecular methods respectively. These genetic tests are core elements of diagnosis and prognostication in high-income countries. They are routinely incorporated in clinical decision making, allowing for the individualization of therapy. However, these tests are largely inaccessible to most patients in Kenya and therefore no data has been reported on this group of patients. The main purpose of this study is to describe the cytogenetic and molecular abnormalities of acute myeloid leukemia patients seen at the hemato-oncology unit of Kenyatta National Hospital. A cross-sectional descriptive study was carried out over a 3-month period on ten patients with a diagnosis of AML. Social demographics and clinical data were collected through a study proforma. A peripheral blood sample was collected for conventional metaphase G-banding technique and next generation sequencing. Particularly, targeted DNA sequencing (Illumina myeloid panel) and whole exome sequencing (WES) were performed. Cytogenetic analysis failed in 10/10 cases. Targeted sequencing was successfully obtained in 8 cases, whereas WES in 7. Cytogenetic studies yielded no results. There were 20 mutations detected across 10 commonly mutated genes. All patients had at least one clinically relevant mutation. Based on ELN criteria, NGS identified three patients with high-risk mutations, affecting TP53 (n = 2) and RUNX1 (n = 1). One patient was classified as favorable (PML-RARA) while 4 were standard risk. However, WT1 mutations associated with unfavorable prognosis were recorded in additional 2 cases. WES showed concordant results with targeted sequencing while unveiling more mutations that warrant further attention. In conclusion, we provide the first molecular profiling study of AML patients in Kenya including application of advanced next generation sequencing technologies, highlighting current limitations of AML diagnostics and treatment while confirming the relevance of NGS in AML characterization.

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PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia.

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PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia.

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