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

ABSTRACT: Protein arginine methyltransferase 5 (PRMT5) belongs to the class II arginine methyltransferases and catalyzes monomethylation and symmetrical dimethylation of arginines on proteins. It has recently emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for a range of malignancies. In this study, we aimed to further elucidate the role of PRMT5 in acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 as well as a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. By using multiplexed quantitative proteomics, we identified PRMT5 substrates 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. Consistent with this, we found that loss of PRMT5 led to changes in alternative splicing. This analysis revealed multiple affected essential genes, linking PRMT5 activity to its loss of function phenotype. Our results show that PRMT5 regulates binding of SRSF1 to mRNAs and proteins in leukemia and provide potential biomarkers for the treatment response to PRMT5 inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE129652 | GEO | 2019/08/20

REPOSITORIES: GEO

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

Project description:Protein arginine methyltransferase 5 (PRMT5) belongs to the class II arginine methyltransferases and catalyzes monomethylation and symmetrical dimethylation of arginines on proteins. It has recently emerged as a promising cancer drug target, and two PRMT5 inhibitors are currently in clinical trials for a range malignancies. Despite the recognized therapeutic potential, it is unclear which PRMT5 functions underlie its oncogenic activity. In this study, we aimed to further understand the role of PRMT5 in acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 as well as a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. By using cutting-edge proteomics techniques we identified PRMT5 substrates 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. Consistent with this, we found that loss of PRMT5 led to changes in alternative splicing. This revealed multiple affected essential genes, linking PRMT5 activity to its loss of function phenotype. Our results show that PRMT5 directly regulates SRSF1 activity in leukemia, and they provide potential biomarkers for the treatment response to PRMT5 inhibitors.

2019-11-08 | PXD013611 | Pride

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

2019-08-21 | PXD014792 | Pride

SAM Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance

Project description:Protein arginine methyltransferase 5 (PRMT5) over-expression in hematological and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with in vitro and in vivo characterization of clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the co-factor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of NSCLC cancer cells, with dose-dependent decreases in symmetric dimethyl arginine (SDMA) levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity to PF-06939999 in NSCLC cells associates with cancer pathways including MYC, cell cycle and spliceosome, and with mutations in splicing factors such as RBM10. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 in the treatment of splicing dysregulated NSCLC.

2021-11-09 | GSE174615 | GEO

Transcriptomic Profile of OCI-AML-20 Cell Line in response to PRMT5 inhibition

Project description:We investigated the role of protein arginine methyltransferase 5 (PRMT5) in leukemia patient cells with inversion of chromosome 3. This rearrangement leads to overexpression of the proto-oncogene EVI1 (ecotropic virus integration site 1). To further investigate the mechanism of PRMT5 dependency in these cells, we performed transcriptome and splicing analyses.

2022-03-23 | GSE163305 | GEO

TDRD6 mediates early steps of spliceosome maturation in primary spermatocytes

Project description:Very little is known about splicing and its regulation in germ cells, particularly during meiosis. This paper describes the role of a male germ cell-specific protein, Tudor containing protein 6 (TDRD6), in assembly of the spliceosome in spermatocytes. We show that in spermatocytes, TDRD6 interacts with the key protein methyl transferase of the splicing pathway PRMT5. PRMT5 methylates arginines in substrate proteins. In a methylation dependent manner, TDRD6 also associates with spliceosomal core protein SmB in the absence of RNA, thus before an RNP-type spliceosome has been assembled. In Tdrd6-/- primary spermatocytes, PRMT5's association with SmB and the arginine dimethylation of SmB are much reduced. Abrogation of arginine methylation impaired the assembly of spliceosomes and the presence of the spliceosomal RNA U5 is aberrantly increased. These deficiencies in spliceosome maturation correlated with decreased numbers of Cajal bodies and gems involved in later stages, i.e. nuclear snRNP maturation. To reveal functional consequences of these deficiencies, transcriptome analysis of primary spermatocytes showed high numbers of splicing defects such as aberrant usage of intron and exons as well as aberrant representation of splice junctions upon TDRD6 loss. This study reveals a novel function of TDRD6 in spliceosome maturation and mRNA splicing in spermatocytes.

2017-03-01 | GSE94791 | GEO

Small-molecule inhibition of PRMT5 activates p53 in erythropoiesis through perturbation of mRNA processing, transport and protein translation

Project description:The protein arginine methyltransferase PRMT5 catalyzes symmetric di-methylation of numerous proteins involved in epigenetic gene regulation, mRNA splicing and DNA repair. Several small molecule inhibitors of PRMT5 are in clinical trials for acute myeloid leukemia, myelodysplasia, lymphoma and metastatic solid tumors. Here, we report the development of a new potent and specific small molecule inhibitor of PRMT5 (CTX-034) that binds and competes for the arginine substrate binding pocket. CTX-034 suppresses erythroid progenitor growth 30-fold more potently than myeloid progenitor growth through activation of p53. Using a combination of RNA-seq and proteomics, we show that PRMT5 binds and methylates numerous proteins required for protein translation including RNA transport (Heterogeneous Nuclear Ribonucleoprotein A1), initiation of translation (Poly(A) Binding Protein Cytoplasmic 1) and ribosomal assembly (Ribosomal Protein S10). Using an in vivo mouse model of JAK2V617F-driven Polycythemia Vera, CTX-034 suppresses the formation of immature erythroblasts as effectively as the JAK inhibitor Ruxolitinib.

2024-02-01 | GSE145285 | GEO

Genetic deletion or small molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML

Project description:The hematological malignancies classified as Mixed Lineage leukemias (MLL) harbor fusions of the MLL1 gene to partners that are members of transcriptional elongation complexes. MLL-rearranged leukemias are associated with extremely poor prognosis and response to conventional therapies and efforts to identify molecular targets are urgently needed. Using mouse models of MLL-rearranged acute myeloid leukemia (AML), here we show that genetic inactivation or small molecule inhibition of the protein arginine methyltransferase PRMT5 exhibit anti-tumoral activity in MLL-fusion protein driven transformation. Genome wide transcriptional analysis revealed that inhibition of PRMT5 methyltransferase activity overrides the differentiation block in leukemia cells without affecting the expression of MLL-fusion direct oncogenic targets. Furthermore, we find that this differentiation block is mediated by transcriptional silencing of the cyclin-dependent kinase inhibitor p21 (CDKN1a) gene in leukemia cells. Our study provides pre-clinical rationale for targeting PRMT5 using small molecule inhibitors in the treatment of leukemias harboring MLL-rearrangements.

2017-07-13 | GSE100820 | GEO

PRMT5-mediated histone arginine methylation antagonizes transcriptional repression by polycomb complex PRC2 (ChIP-seq)

Project description:Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues in histones H3 and H4, marks generally associated with transcriptional repression. However, we found that PRMT5 inhibition (or depletion) led to more genes being down-regulated than up-regulated, indicating that PRMT5 can also act as a transcriptional activator. Indeed, the global level of histone H3K27me3 increases in PRMT5 deficient cells. Although PRMT5 does not directly affect PRC2 enzymatic activity, methylation of histone H3 by PRMT5 abrogates its subsequent methylation by PRC2. Treating AML cells with an EZH2 inhibitor partially restored the expression of approximately 50% of the genes that are initially down-regulated by PRMT5 inhibition, suggesting that the increased H3K27me3 contributes to the transcription repression of these genes. Interestingly, the growth inhibitory effect of PRMT5 inhibition was also partially rescued by combined treatment with EZH2 inhibitor in several leukemia cell lines. Thus, PRMT5-mediated crosstalk between histone marks contributes to its functional effects.

2021-05-30 | GSE142764 | GEO

PRMT5-mediated histone arginine methylation antagonizes transcriptional repression by polycomb complex PRC2 (RNA-seq)

2021-05-30 | GSE132407 | GEO

Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation

Project description:Cancer-associated mutations in RNA splicing factors commonly occur in myeloid and lymphoid leukemias as well as a variety of solid tumors and confer dependence on wild-type (WT) splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here we identify that inhibiting symmetric (SDMA) or asymmetric dimethyl arginine methylation (ADMA), mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs) respectively, reduces splicing fidelity and results in strong preferential killing of spliceosomal mutant leukemias over WT counterparts. Consistent with this, proteomic analyses identified RNA binding proteins and splicing factors as the most enriched PRMT5 and/or PRMT Type I substrates in leukemia. Accordingly, combined PRMT5/type I PRMT inhibition resulted in synergistic cell killing and pronounced effects on splicing compared with inhibiting either enzymatic activity alone. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer.

2019-07-30 | PXD012007 | Pride

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