![]() The prognostic significance of the target genes was analyzed using publicly available gene expression data of MM patients (TT2/3 and HM cohorts). Here, we used bio-informatic tools to identify novel targets involved in DNA repair and epigenetics and which are associated with high-risk myeloma. Therefore, the need for effective therapeutic options remains high. Subsets of patients have high-risk features linked with dismal outcome. Multiple myeloma (MM) is an incurable clonal plasma cell malignancy. Thus, we propose a therapeutic strategy in lymphoma that combines PRMT5 with MSI2 or BCL-2 inhibition. BCL-2 depletion or inhibition with venetoclax synergizes with a PRMT5 inhibitor by inducing reduced cell growth and apoptosis. Dual MSI2 and PRMT5 inhibition further blocks c-MYC and BCL-2 translation. Ro reduces MSI2 binding to its global targets and dual treatment of Ro and PRMT5 inhibitors result in synergistic gene expression changes including cell cycle, P53 and MYC signatures. MSI2 depletion and pharmacological inhibition using Ro 08-2750 (Ro) both synergize with GSK-591 to reduce cell growth. ![]() PRMT5 expression correlates with MSI2 expression in lymphoma patients. TP53 deletion and TP53R248W mutation are biomarkers of resistance to GSK-591. We identify TP53 and RNA-binding protein MUSASHI2 (MSI2) as the top-ranked sensitizer and driver of resistance to specific PRMT5i, GSK-591, respectively. To identify drivers of sensitivity and resistance to Protein Arginine Methyltransferase 5 (PRMT5) inhibition, we perform a genome-wide CRISPR/Cas9 screen. This study highlights evidence of novel selective anticancer activity of AMI-1 in combination with CKI in lung carcinoma. The above findings demonstrated that AMI-1 has established antineoplastic activity and this role may be associated with affecting the function of eIF4E via inhibiting PRMT5 activity or protein levels in lung carcinoma. Of note, combined and CKI markedly enhanced the anticancer efficacy CKI in lung carcinoma. Moreover, AMI-1 suppressed tumor growth, decreased H3R8me2s and H4R3me2s accumulation, down-regulated eIF4E expression and increased p53 expression in lung carcinoma xenografts of BALB/c nude mice. Meanwhile, AMI-1 suppressed cell migration, enhanced apoptosis, induced cell cycle arrest, inhibited PRMT5 expression and histone H3R8 and H4R3 symmetric di-methylation (H3R8me2s and H4R3me2s) accumulation, down-regulated the expression of eukaryotic translation initiation factor 4E (eIF4E) in lung carcinoma cells. Here we found that cell viability and colony formation were inhibited after the incubation of AMI-1. Compound Kushen injection (CKI) is a mixture of natural compounds extracted from Kushen and Baituling, which are mainly used to stop in cancer pain and bleeding. Protein arginine methyltransferase 5 (PRMT5) is overexpressed in lung carcinoma, which promotes tumor cell proliferation, survival, migration and invasion. PRMT5 inhibitors have a strong therapeutic potential, as phase I clinical trials in hematological malignancies that use these molecules show promising results, thus, underlining PRMT inhibitors as useful therapeutic tools for cancer treatment in the future. They show a significant effect by reducing cell viability and increasing the overall survival of mice. Chemical tools have been developed to inhibit the activity of PRMTs and have been tested in several models of hematological malignancies, including primary samples from patients, xenografts into immunodeficient mice, mouse models, and human cell lines. PRMT enzymatic activity is necessary for many cellular processes in hematological malignancies, such as the activation of cell cycle and proliferation, inhibition of apoptosis, DNA repair processes, RNA splicing, and transcription by methylating histone tails’ arginine. During the formation and maturation of the different types of blood cells, PRMTs play a central role by controlling cell differentiation at the transcriptional level. There are nine protein arginine methyltransferases (PRMTs) in mammals, divided into subgroups depending on the methylation they form on a molecule of arginine. Arginine methylation is a common post-translational modification affecting protein activity and the transcription of target genes when methylation occurs on histone tails.
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