The genomic landscape of Vk*MYC myeloma highlights shared pathways of transformation between mice and humans

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 7, 2024

Abstract Multiple myeloma (MM) is a heterogeneous disease characterized by frequent MYC translocations. Sporadic activation in the germinal center of genetically engineered Vk*MYC mice sufficient to induce plasma cell tumors which variety secondary mutations are spontaneously acquired and selected over time. Analysis 119 reveals recurrent copy number alterations, structural variations, chromothripsis, driver mutations, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) mutational activity, progressive decrease immunoglobulin transcription that inversely correlates with proliferation. Moreover, we identify insertional mutagenesis endogenous retro-elements as murine specific mechanism activate NF-kB IL6 signaling pathways shared human MM. Despite increased genomic complexity associated progression, advanced remain dependent on . In summary, here credential mouse unique resource explore MM evolution describe fully annotated collection diverse immortalized tumors.

Language: Английский

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Integrated pan-cancer analysis reveals the immunological and prognostic potential of RBFOX2 in human tumors

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: May 31, 2024

Background The role of RNA-binding fox one homolog 2 (RBFOX2) in the progression multiple tumors is increasingly supported by evidence. However, unclearness pertaining to expression RBFOX2, its prognostic potential, and correlation with tumor microenvironment (TME) pan-cancer persists. This study aims comprehensively investigate immunological value RBFOX2. Methods Cancer Genome Atlas Gene Expression Omnibus Genotype-Tissue (GTEx), TIMER2.0, Kaplan-Meier (K–M) Plotter, University Alabama at Birmingham data analysis Portal (UALCAN), cbioportal, Profiling Interactive Analysis (GEPIA2) were utilized for a systematic included studying expression, value, DNA methylation, enrichment analysis, immune infiltration cells, immune-related genes. Additionally, qRT-PCR, CCK-8, colony formation, transwell assays, immunohistochemistry employed analyze biological function RBFOX2 liver cancer. Results Variations have been observed across diverse identified as indicators unfavorable prognosis. It closely linked checkpoints, chemokines, chemokine receptors TME. Higher levels significantly associated low response poor prognosis patients non-small cell lung cancer (NSCLC) melanoma who receive immunotherapy. Furthermore, methylation varies different types has shown better BLCA, BRCA, CESC, COAD, DLBC, HNSC, LAML, LGG, LUAD, PAAD, SKCM THYM. Interestingly, was found be lower hepatocellular carcinoma (HCC) patients’ tissues compared their paired adjacent tissues. In vitro studies that knockdown promotes growth metastasis cells. Conclusion investigates between indicates potential inhibit

Language: Английский

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Regulatory T cells hamper the efficacy of T-cell-engaging bispecific antibody therapy

Haematologica, Journal Year: 2023, Volume and Issue: 109(3), P. 787 - 798

Published: Sept. 28, 2023

T-cell-engaging bispecific antibodies (T-BsAb) have produced impressive clinical responses in patients with relapsed/refractory B-cell malignancies, although treatment failure remains a major challenge. Growing evidence suggests that complex interplay between immune cells and tumor is implicated the mechanism of action therefore, understanding regulatory mechanisms might provide clue for how to improve efficacy T-BsAb therapy. Here, we investigated functional impact T (Treg) on anti-tumor immunity elicited by In preclinical model myeloma, activation expansion Treg bone marrow were observed response anti-B-cell maturation antigen (BCMA) triggered generation induced from human conventional CD4 after co-culture cells. Moreover, directly activated freshly isolated circulating cells, leading production interleukin-10 inhibition T-BsAb-mediated CD8 T-cell responses. The was also seen samples myeloma ex vivo T-BsAb, further supporting an homeostasis. Importantly, transient ablation combination therapy dramatically improved effector lymphocyte activities disease control model, prolonged survival. Together, this information therapy-induced critically regulates therapy, important implications improving such treatment.

Language: Английский

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Clearing soluble MIC reverses the impaired function of natural killer cells from patients with multiple myeloma

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(1), P. e007886 - e007886

Published: Jan. 1, 2024

Background Major histocompatibility complex (MHC) class I chain-related protein (MIC) is a stress-induced ligand released from multiple myeloma (MM) cells during progression, and soluble MIC impairs natural killer group 2D (NKG2D) activating receptor-mediated recognition function of (NK) cells. However, whether clearing with monoclonal antibody (mAb) can restore NK cell activity MM patients remains undetermined. Methods We analyzed The Cancer Genome Atlas (TCGA) Multiple Myeloma Research Foundation (MMRF) CoMMpass data set to examine the prognostic significance expression in MM. examined level paired peripheral blood (PB) bone marrow (BM) plasma at diagnosis by ELISA. evaluated correlation between immunophenotype multicolor flow cytometry. also generated MIC-overexpressing line characterized cytotoxic patient presence MIC, impact humanized mAb (huB10G5). Results characterize importance MICA revealing significantly better overall survival high TCGA MMRF set. more highly elevated than precursor stages, concentration higher BM PB. was correlated burden, while it negatively frequency NKG2D + diagnostic aspirates patients. Soluble downregulated decreased cytotoxicity ex vivo , which were reversed MIC-clearing (huB10G5) enhanced degranulation Conclusions Our findings indicate targeting huB10G5 might be viable therapeutic approach promote NKG2D-dependent cellular immunotherapy outcome

Language: Английский

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Integrating p53-associated genes and infiltrating immune cell characterization as a prognostic biomarker in multiple myeloma

Heliyon, Journal Year: 2024, Volume and Issue: 10(8), P. e30123 - e30123

Published: April 1, 2024

BackgroundTumor genetic anomalies and immune dysregulation are pivotal in the progression of multiple myeloma (MM). Accurate patient stratification is essential for effective MM management, yet current models fail to comprehensively incorporate both molecular profiles.MethodsWe examined 776 samples from MMRF CoMMpass database, employing univariate regression with LASSO CIBERSORT algorithms identify 15 p53-related genes six cells prognostic significance MM. A p53-TIC (tumor-infiltrating cells) classifier was constructed by calculating scores using bootstrap-multicox method, which further validated externally (GSE136337) through ten-fold internal cross-validation its predictive reliability robustness.ResultsThe demonstrated excellent performance predicting prognosis Specifically, patients p53low/TIChigh subgroup had most favorable lowest tumor mutational burden (TMB). Conversely, those p53high/TIClow subgroup, least highest TMB, were predicted have best anti-PD1 anti-CTLA4 response rate (40%), can be explained their higher expression PD1 CTLA4. The three-year area under curve (AUC) 0.80 total sample.ConclusionsOur study highlights potential an integrated analysis p53-associated TIC aiding clinical decision-making patients. This finding underscores comprehending intricate interplay between abnormalities dysfunction Further research into this may lead development more treatment strategies.

Language: Английский

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