A MIR17HG-derived long noncoding RNA provides an essential chromatin scaffold for protein interaction and myeloma growth

Morelli, Eugenio; Fulciniti, Mariateresa; Samur, Mehmet K.; Ribeiro, Caroline F.; Wert-Lamas, León; Henninger, Jonathan E.; Gullà, Annamaria; Samur, Anıl Aktaş; Todoerti, Katia; Talluri, Srikanth; Park, Woojun D; Federico, Cinzia; Scionti, Francesca; Amodio, Nicola; Bianchi, Giada; Johnstone, Megan; Liu, Na; Gramegna, Doriana; Maisano, Domenico; Russo, Nicola Antonino; Lin, Charles Y.; Tai, Yu‐Tzu; Neri, Antonino; Chauhan, Dharminder; Hideshima, Teru; Shammas, Masood A.; Tassone, Pierfrancesco; Gryaznov, Sergei M.; Young, Richard A.; Anderson, Kenneth C.; Novina, Carl D.; Loda, Massimo; Munshi, Nikhil C.

doi:10.1182/blood.2022016892

Cited by 16 publications

(5 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A lncRNA derived from the MIR17HG, lnc-17–92, has been found to accelerate tumor growth by upregulating ACACA (an ACC1 encoding gene). Disrupting lnc-17–92 with an antisense oligonucleotide yielded significant tumor suppression in vitro and in vivo [ 26 ]. Overall, the dynamics of FA metabolism—both its synthesis and breakdown—are crucial in the progression, manifestation, and treatment resistance of multiple myeloma.…”

Section: Discussionmentioning

confidence: 99%

Identification of lipid metabolism-related gene signature in the bone marrow microenvironment of multiple myelomas through deep analysis of transcriptomic data

Feng,

Wang,

Cao

et al. 2024

Clin Exp Med

View full text Add to dashboard Cite

Dysregulated lipid metabolism in the bone marrow microenvironment (BMM) plays a vital role in multiple myeloma (MM) development, progression, and drug resistance. However, the exact mechanism by which lipid metabolism impacts the BMM, promotes tumorigenesis, and triggers drug resistance remains to be fully elucidated.By analyzing the bulk sequencing and single-cell sequencing data of MM patients, we identified lipid metabolism-related genes differential expression significantly associated with MM prognosis, referred to as LMRPgenes. Using a cohort of ten machine learning algorithms and 117 combinations, LMRPgenes predictive models were constructed. Further exploration of the effects of the model risk score (RS) on the survival status, immune status of patients with BMM, and response to immunotherapy was conducted. The study also facilitated the identification of personalized therapeutic strategies targeting specified risk categories within patient cohorts.Analysis of the scRNA-seq data revealed increased lipid metabolism-related gene enrichment scores (LMESs) in erythroblasts and progenitor, malignant, and Tprolif cells but decreased LMESs in lymphocytes. LMESs were also strongly correlated with most of the 50 hallmark pathways within these cell populations. An elevated malignant cell ratio and reduced lymphocytes were observed in the high LMES group. Moreover, the LMRPgenes predictive model, consisting of 14 genes, showed great predictive power. The risk score emerged as an independent indicator of poor outcomes. Inverse relationships between the RS and immune status were noted, and a high RS was associated with impaired immunotherapy responses. Drug sensitivity assays indicated the effectiveness of bortezomib, buparlisib, dinaciclib, staurosporine, rapamycin, and MST-312 in the high-RS group, suggesting their potential for treating patients with high-RS values and poor response to immunotherapy. Ultimately, upon verification via qRT-PCR, we observed a significant upregulation of ACBD6 in NDMM group compared to the control group.Our research enhances the knowledge base regarding the association between lipid metabolism-related genes (LMRGs) and the BMM in MM patients, offering substantive insights into the mechanistic effects of the BMM mediated by LMRGs. Graphical abstract

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of lipid metabolism-related gene signature in the bone marrow microenvironment of multiple myelomas through deep analysis of transcriptomic data

Feng,

Wang,

Cao

et al. 2024

Clin Exp Med

View full text Add to dashboard Cite

show abstract

“…ACC1 stands as a rate-limiting enzyme in fatty acid synthesis, primarily residing in the cytoplasm and catalyzing the conversion of acetyl-CoA into malonyl-CoA [53]. Recent reports have substantiated the close association of ACC1 with the development and progression of various cancers [54,55]. Our study has further revealed that circE7 promotes ACC1 dephosphorylation by directly binding to ACC1, leading to activated ACC1 catalyzing the conversion of acetyl-CoA into malonyl-CoA, consequently reducing acetyl-CoA levels in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Circular RNA circE7 Encoded by Human Papillomavirus Facilitates Immune Evasion in Head and Neck Squamous Cell Carcinoma through Epigenetically Downregulating Galectin-9

Xiong,

Ge,

Guo

et al. 2023

Preprint

View full text Add to dashboard Cite

Immune evasion represents a crucial milestone in the progression of cancer and serves as the theoretical foundation for tumor immunotherapy. Currently, immune checkpoint inhibitors such as anti-PD-1/PD-L1 have shown promising therapeutic efficacy in clinical settings for various tumors. However, a significant proportion of tumor patients fail to benefit from this class of immune checkpoint inhibitors, implying potential involvement of other immune checkpoint molecules in tumor immune escape. In this study, we unveiled a negative association between Human Papillomavirus (HPV)-encoded circular RNA circE7 and the presence of infiltrating CD8+ T cells in head and neck squamous cell carcinoma (HNSCC). Both in vitro and in vivo experiments demonstrated that circE7 suppressed the function and activity of T cells by downregulating the transcription of LGALS9, which encodes the galectin-9 protein. The unexpected molecular mechanism involved the binding of circE7 to acetyl-CoA carboxylase 1 (ACC1), enhancing its dephosphorylation, and thereby activation of ACC1, which resulted in a reduction in the acetylation level of H3K27 in the promoter region of LGALS9 gene and subsequent downregulation of galectin-9 expression. Notably, galectin-9 interacts with immune checkpoint molecules TIM-3 and PD-1 present on T cell surface, triggering T cells to secrete cytotoxic cytokines and hindering T cell apoptosis. In essence, HPV-mediated downregulation of galectin-9 expression through circE7 impairs T cell function and activity, ultimately promoting immune evasion in HNSCC. Importantly, we confirmed that a combination of monoclonal antibodies simultaneously targeting TIM-3 and PD-1 significantly improved the immunotherapeutic efficacy in HNSCC both in vitro and in animal models. Our study unveils a novel mechanism through which HPV promotes immune evasion in HNSCC via circE7-mediated epigenetic modification, offering a new therapeutic strategy for enhanced HNSCC immunotherapy.

show abstract

“…We recently demonstrated that a MIR17 host gene (MIR17HG)-derived long non-coding RNA, named lnc-17–92, acts as a chromatin scaffold for the functional interaction between the c-MYC onco-protein and WDR82, a regulatory component of the SET1 methyltransferase complex which catalyzes histone H3 Lys-4 (H3K4) methylation (mono-, di-, tri-) at the transcriptional start sites of active loci, thus promoting the expression of ACACA gene, encoding ACC1. Targeting MIR17HG pre-RNA with novel antisense molecules (ASOs) disrupted the transcriptional and functional activities of lnc-17–92, causing potent anti-tumor effects in preclinical models both in vitro and in vivo, which was associated with a decrease in de novo lipogenesis [ 73 ].…”

Section: Lipid Metabolic Vulnerabilities Of MMmentioning

confidence: 99%

Lipid metabolic vulnerabilities of multiple myeloma

Torcasio,

Gallo Cantafio,

Ikeda

et al. 2023

Clin Exp Med

Self Cite

View full text Add to dashboard Cite

Multiple myeloma (MM) is the second most common hematological malignancy worldwide, characterized by abnormal proliferation of malignant plasma cells within a tumor-permissive bone marrow microenvironment. Metabolic dysfunctions are emerging as key determinants in the pathobiology of MM. In this review, we highlight the metabolic features of MM, showing how alterations in various lipid pathways, mainly involving fatty acids, cholesterol and sphingolipids, affect the growth, survival and drug responsiveness of MM cells, as well as their cross-talk with other cellular components of the tumor microenvironment. These findings will provide a new path to understanding the mechanisms underlying how lipid vulnerabilities may arise and affect the phenotype of malignant plasma cells, highlighting novel druggable pathways with a significant impact on the management of MM.

show abstract

A MIR17HG-derived long noncoding RNA provides an essential chromatin scaffold for protein interaction and myeloma growth

Cited by 16 publications

References 67 publications

Identification of lipid metabolism-related gene signature in the bone marrow microenvironment of multiple myelomas through deep analysis of transcriptomic data

Identification of lipid metabolism-related gene signature in the bone marrow microenvironment of multiple myelomas through deep analysis of transcriptomic data

Circular RNA circE7 Encoded by Human Papillomavirus Facilitates Immune Evasion in Head and Neck Squamous Cell Carcinoma through Epigenetically Downregulating Galectin-9

Lipid metabolic vulnerabilities of multiple myeloma

Contact Info

Product

Resources

About