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Targeting Arginine Methylation Suppresses Cancer Stem Cell Maintenance and Elicits cGAS-mediated anti-Cancer Immunity

ABSTRACT: Current anti-cancer therapies cannot eliminate all the cancer cells, which hijack normal arginine methylation as a means to promote their own maintenance via unknown mechanisms. Herein, we show that targeting protein arginine methyltransferase 9 (PRMT9), whose activities are elevated in leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic Type-I Interferon (IFN-I)-associated immunity. PRMT9 ablation in AML cells decreased arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cGAS, which underlies the IFN-I response. Genetically activating cGAS in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-PD1 in eradicating PRMT9-proficient cancers, including AML and lymphoma. We conclude that PRMT9 governs LSCs survival and immune evasion, and that combining a PRMT9 inhibitor with an immune checkpoint inhibitor represents a novel anti-cancer strategy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217195 | GEO | 2023/11/03

REPOSITORIES: GEO

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Targeting Arginine Methylation Suppresses Cancer Stem Cell Maintenance and Elicits cGAS-mediated anti-Cancer Immunity II

Project description:Current anti-cancer therapies cannot eliminate all the cancer cells, which hijack normal arginine methylation as a means to promote their own maintenance via unknown mechanisms. Herein, we show that targeting protein arginine methyltransferase 9 (PRMT9), whose activities are elevated in leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic Type-I Interferon (IFN-I)-associated immunity. PRMT9 ablation in AML cells decreased arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cGAS, which underlies the IFN-I response. Genetically activating cGAS in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-PD1 in eradicating PRMT9-proficient cancers, including AML and lymphoma. We conclude that PRMT9 governs LSCs survival and immune evasion, and that combining a PRMT9 inhibitor with an immune checkpoint inhibitor represents a novel anti-cancer strategy.

2023-12-07 | GSE220452 | GEO

Targeting Arginine Methylation Suppresses Cancer Stem Cell Maintenance and Elicits cGAS-mediated anti-Cancer Immunity

2023-11-03 | GSE217396 | GEO

Characterization of Arginine Methylation in Cancer Cell using LC-MS/MS

Project description:Protein arginine methyltransferase 9 (PRMT9) activity has been observed to be elevated in cancer patients, including many types of leukemias, correlating with poor prognosis and decreased response to immune checkpoint inhibitors. By targeting PRMT9, we can eliminate PRMT9-proficient/immune-cold cancers via mechanisms such as Type-I Interferon associated immunity. Deleting PRMT9 resulted in a decrease in arginine methylation of regulators involved in RNA translation and DNA damage response. Through global proteomics and SILAC methyl(R) enrichment, we characterized arginine methylation changes in AML cell lines via LC-MS/MS.

2024-01-11 | PXD039441 | Pride

High throughput sequencing identifies alternative splicing events regulated by PRMT9

Project description:The human genome encodes a family of nine protein arginine methyltransferases (PRMT1-9). Different members of this enzyme family catalyze different types of protein methylation at the terminal nitrogen atoms of arginine residues, forming monomethylated arginine (MMA), asymmetrically dimethylated arginine (ADMA) and symmetrically dimethylated arginine (SDMA). The last member of this family, PRMT9, is characterized in detail here. We identify two spliceosome-associated proteins, SAP145 (SF3B2) and SAP49 (SF3B4), as PRMT9 binding partners, linking PRMT9 to U2snRNP maturation. We show that SAP145 is methylated by PRMT9 at arginine 508 (R508). Amino acid analysis and a methyl-specific antibody revealed the formation of MMA and SDMA, and PRMT9 thus joins PRMT5 as the only mammalian enzymes that can deposit the SDMA mark. Methylation of the SAP145R508 generates a binding site for the Tudor domain of SMN, and RNA-seq analysis reveals gross splicing changes when PRMT9 levels are attenuated. These studies identify PRMT9 as a non-histone methyltransferase that primes the U2snRNP for interaction with SMN. RNA sequencing was carried out using RNA samples from two biological replicates of control and PRMT9 knockdown HeLa cells.

2015-01-22 | E-GEOD-63953 | biostudies-arrayexpress

High throughput sequencing identifies alternative splicing events regulated by PRMT9

2015-01-22 | GSE63953 | GEO

Type I Innate Lymphoid Cells Control Leukemia Stem Cell Fate and Limit Development of Acute Myeloid Leukemia [2]

Project description:Type I innate lymphoid cells (ILC1s) are critical regulators of inflammation and immunity in mammalian tissues. However, their functional roles in cancer are largely undefined. We found that a high concentration of normal murine ILC1s induced leukemia stem cell (LSC) apoptosis. At a lower concentration, ILC1s prevented LSCs from differentiating into leukemia progenitors and promoted their differentiation into non-leukemic cells, thus blocking the production of terminal myeloid blasts. All of these effects, which required ILC1s to produce interferon-γ after cell–cell contact with LSCs, converged to suppress leukemogenesis in vivo. Conversely, ILC1s’ anti-leukemia potential waned when JAK-STAT and PI3K-AKT signaling was inhibited. The relevant anti-leukemic properties of normal ILC1s were operative in humans and impaired in AML patients. Collectively, our findings reveal crucial functions of ILC1s as anti-cancer immune cells seemingly suitable for AML immunotherapy, and provide a new potential strategy to treat AML and/or prevent relapse of the disease.

2022-03-19 | GSE198782 | GEO

Type I Innate Lymphoid Cells Control Leukemia Stem Cell Fate and Limit Development of Acute Myeloid Leukemia [1]

2022-03-19 | GSE198781 | GEO

The important role of GPR84 in MLL leukemogenesis

Project description:Beta-catenin signaling is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML), yet the upstream regulators that can augment this pathway are unknown. Through genome-wide gene expression analysis and functional studies, we identified an important role for GPR84 in MLL AML. Suppression of GPR84 significantly inhibited cell growth in pre-LSCs, reduced LSC frequency and impaired reconstitution of MLL AML. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a transduced hematopoietic stem cells (HSCs). Our microarray analysis demonstrated that GPR84 overexpression significantly up-regulated a small set of MLL-fusion targets and beta-catenin co-effectors, and down-regulated a hematopoietic cell cycle inhibitor. These data thus reveal a previously unrecognized role of GPR84 in the maintenance of fully developed AML by sustaining aberrant beta-catenin signaling in LSCs. HSC-derived Hoxa9/Meis1a pre-LSCs were transduced with GPR84 cDNA or empty vector, and replated in methylcellulose supplemented with cytokines. Each group contains triplicate samples.

2014-10-15 | E-MTAB-1932 | biostudies-arrayexpress

PRMT9-catalyzed SF3B2 methylation regulates RNA splicing and synapse development

Project description:Human genome encodes nine protein arginine methyltransferases (PRMT1–9), which catalyze three types of arginine methylation: monomethylation (MMA), asymmetric dimethylation (ADMA), and symmetric dimethylation (SDMA). These modifications can alter protein-protein and protein-nucleic acid interactions and play critical roles in transcription regulation and RNA metabolism. A few years ago, we characterized the newest member of the PRMT family–PRMT9 as a SDMA modifying enzyme and identified the splicing factor SF3B2 as its methylation substrate, linking its function to pre-mRNA splicing. However, the biological function of PRMT9 and the molecular mechanism by which PRMT9-catalyzed SF3B2 arginine methylation regulates pre-mRNA splicing remain largely unknown. Here, by charactering an intellectual disability patient-derived PRMT9 mutation (G189R) and establishing a Prmt9 conditional knockout (cKO) mouse model, we uncovered an important function of PRMT9 in neuronal development. We found that G189R mutation completely abolishes PRMT9 methyltransferase activity and destabilizes the protein by promoting its ubiquitination and proteasome degradation. PRMT9 loss in hippocampal neurons alters RNA splicing of ~1800 transcripts, which likely account for the abnormal synapse development and impaired learning and memory observed in the Prmt9 cKO mouse. Mechanistically, we discovered a critical protein-RNA interaction between the arginine 508 (R508) of SF3B2, the site that is exclusively methylated by PRMT9, and the pre-mRNA anchoring site, a cis-regulatory element located upstream of the branch point sequence (BPS). Additionally, we provide strong evidence that supports SF3B2 being the major and likely only substrate of PRMT9, thus highlighting the conserved function of PRMT9/SF3B2 axis in pre-mRNA splicing regulation.

2023-08-27 | GSE212192 | GEO

PRMT1-mediated FLT3 arginine methylation is required for maintenance of FLT3-ITD+ Acute Myeloid Leukemia

Project description:The presence of FLT3-ITD mutations in patients with acute myeloid leukemia (AML) is associated with poor clinical outcome. FLT3 tyrosine kinase inhibitors (TKIs), although effective in kinase ablation, do not eliminate FLT3-ITD+ leukemia stem cells (LSCs) which are potential sources of disease relapse, prompting us to ask whether FLT3-ITD protein regulates the AML LSCs survival through a kinase-independent mechanism. Here, we show that expression of PRMT1, the primary type I arginine methyltransferase, significantly increases in LSC-enriched CD34+CD38- populations relative to normal counterparts. Genetic PRMT1 depletion blocked AML CD34+ cell survival, and had more potent effects in AML cells from patients harboring FLT3-ITD. Our genome wide analysis of gene expression and PRMT1 conditional KO mouse study confirmed that PRMT1 preferentially cooperates with FLT3-ITD contributing to AML cell maintenance. Mechanistically, PRMT1 catalyzed FLT3-ITD protein methylation at arginines 972/973, and PRMT1 promoted leukemia cell growth in a FLT3 methylation-dependent manner. Moreover, effects of FLT3-ITD methylation in AML cells were in part due to crosstalk with FLT3-ITD phosphorylation at tyrosine 969 (Y969). Importantly, FLT3 methylation persisted in FLT3-ITD+ AML cells following TKI (AC220) treatment, indicating that methylation occurs independently of kinase activity. Finally, in both patient-derived xenograft (PDX) and murine AML models, combined administration of AC220 with a type I PRMT inhibitor (MS023) enhanced elimination of FLT3-ITD+ AML relative to AC220 treatment alone. Our study demonstrates that PRMT1-mediated FLT3 methylation promotes LSC activity and suggests that combining PRMT1 inhibition with FLT3 TKI treatment could be a promising approach to selectively target FLT3-ITD+ LSCs.

2021-11-10 | GSE122435 | GEO

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