Genetic variants as biomarkers for progression and resistance in multiple myeloma

Montel, R.; Gregory, Matthew A.; Chu, Tin-Chun; Cottrell, Jessica; Bitasktsis, Constantine; Chang, Sulie L.

doi:10.1016/j.cancergen.2020.12.001

Cited by 6 publications

(3 citation statements)

References 6 publications

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“…However, the exact mechanism by which immune cells, especially activated CD4+ T cell subsets, affect MM remains unclear. To mention, some of the genes in our signature has already been implicated in MM, for instance, ALOX12B variants has been proposed as a biomarker for progression and resistance in MM ( 59 ). CDKN2A has previously been found to be differentially expressed in MM ( 60 )., and its overexpression has been correlated with poor OS in MM ( 61 ).…”

Section: Discussionmentioning

confidence: 99%

Systematic discrimination of the repetitive genome in proximity of ferroptosis genes and a novel prognostic signature correlating with the oncogenic lncRNA CRNDE in multiple myeloma

et al. 2022

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Emerging insights into iron-dependent form of regulated cell death ferroptosis in cancer have opened a perspective for its use in cancer therapy. Of interest, a systematic profiling of ferroptosis gene signatures as prognostic factors has gained special attention in several cancers. Herein, we sought to investigate the presence of repetitive genomes in the vicinity of ferroptosis genes that may influence their expression and to establish a prognostic gene signature associated with multiple myeloma (MM). Our analysis showed that genes associated with ferroptosis were enriched with the repetitive genome in their vicinity, with a strong predominance of the SINE family, followed by LINE, of which the most significant discriminant values were SINE/Alu and LINE/L1, respectively. In addition, we examined in detail the performance of these genes as a cancer risk prediction model and specified fourteen ferroptosis-related gene signatures, which identified MM high-risk patients with lower immune/stromal scores with higher tumor purity in their immune microenvironment. Of interest, we also found that lncRNA CRNDE correlated with a risk score and was highly associated with the majority of genes comprising the signature. Taken together, we propose to investigate the molecular impact of the repetitive genome we have highlighted on the local transcriptome of ferroptosis genes in cancer. Furthermore, we revealed a genomic signature/biomarker related to ferroptosis that can be used to predict the risk of survival in MM patients.

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Section: Discussionmentioning

confidence: 99%

Systematic discrimination of the repetitive genome in proximity of ferroptosis genes and a novel prognostic signature correlating with the oncogenic lncRNA CRNDE in multiple myeloma

et al. 2022

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“…A set of 114 DEGs in myeloma plasma cells involved in the progression of the disease were collected from different scientific publications 11 - 47 and databases ( https://www.ncbi.nlm.nih.gov/ ). The following search terms were used: multiple myeloma, gene expression, heterogeneity, mutational profiles, and genetic predisposition.…”

Section: Methodsmentioning

confidence: 99%

Multiple Myeloma: Bioinformatic Analysis for Identification of Key Genes and Pathways

Saadoune

Nouadi

Hamdaoui

et al. 2022

Bioinform Biol Insights

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Multiple myeloma (MM) is a hematological malignancy in which monoclonal plasma cells multiply in the bone marrow and monoclonal immunoglobulins are overproduced in older people. Several molecular and cytogenetic advances allow scientists to identify several genetic and chromosomal abnormalities that cause the disease. The comprehension of the pathophysiology of MM requires an understanding of the characteristics of malignant clones and the changes in the bone marrow microenvironment. This study aims to identify the central genes and to determine the key signaling pathways in MM by in silico approaches. A list of 114 differentially expressed genes (DEGs) is important in the prognosis of MM. The DEGs are collected from scientific publications and databases ( https://www.ncbi.nlm.nih.gov/ ). These data are analyzed by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) software ( https://string-db.org/ ) through the construction of protein-protein interaction (PPI) networks and enrichment analysis of the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, by CytoHubba, AutoAnnotate, Bingo Apps plugins in Cytoscape software ( https://cytoscape.org/ ) and by DAVID database ( https://david.ncifcrf.gov/ ). The analysis of the results shows that there are 7 core genes, including TP53; MYC; CDND1; IL6; UBA52; EZH2, and MDM2. These top genes appear to play a role in the promotion and progression of MM. According to functional enrichment analysis, these genes are mainly involved in the following signaling pathways: Epstein-Barr virus infection, microRNA pathway, PI3K-Akt signaling pathway, and p53 signaling pathway. Several crucial genes, including TP53, MYC, CDND1, IL6, UBA52, EZH2, and MDM2, are significantly correlated with MM, which may exert their role in the onset and evolution of MM.

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“…Cytogenetic/genetic/epigenetic instability leads to the stepwise and branching clonal evolution in myeloma cells, resulting in multiple molecularly heterogeneous subclones [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. The activation of oncogenic driver signals, such as MYC, RAS/ERK, PI3K/AKT, and NF-κB, as well as the dysfunction/loss of pivotal tumor suppressors, such as TP53 or CDKN2C, cooperatively and sometimes compensatively promote the disease progression, the aggressiveness, and treatment-resistant phenotype of tumor cells [ 3 , 6 , 10 , 11 , 12 , 13 , 14 , 15 ]. Cell-extrinsic tumor microenvironment supports the survival and proliferation of myeloma cells via adhesion molecules, soluble factors, or extracellular vesicles, and also protects myeloma cells from cytotoxic insults [ 6 , 16 , 17 , 18 ], whereas the disruption of tumor immune surveillance system allows disease expansion [ 19 , 20 , 21 , 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

The Rationale for the Dual-Targeting Therapy for RSK2 and AKT in Multiple Myeloma

Isa

Horinaka

Tsukamoto

et al. 2022

IJMS

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Multiple myeloma (MM) is characterized by remarkable cytogenetic/molecular heterogeneity among patients and intraclonal diversity even in a single patient. We previously demonstrated that PDPK1, the master kinase of series of AGC kinases, is universally active in MM, and plays pivotal roles in cell proliferation and cell survival of myeloma cells regardless of the profiles of cytogenetic and genetic abnormalities. This study investigated the therapeutic efficacy and mechanism of action of dual blockade of two major PDPK1 substrates, RSK2 and AKT, in MM. The combinatory treatment of BI-D1870, an inhibitor for N-terminal kinase domain (NTKD) of RSK2, and ipatasertib, an inhibitor for AKT, showed the additive to synergistic anti-tumor effect on human MM-derived cell lines (HMCLs) with active RSK2-NTKD and AKT, by enhancing apoptotic induction with BIM and BID activation. Moreover, the dual blockade of RSK2 and AKT exerted robust molecular effects on critical gene sets associated with myeloma pathophysiologies, such as those with MYC, mTOR, STK33, ribosomal biogenesis, or cell-extrinsic stimuli of soluble factors, in HMCLs. These results provide the biological and molecular rationales for the dual-targeting strategy for RSK2 and AKT, which may overcome the therapeutic difficulty due to cytogenetic/molecular heterogeneity in MM.

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Genetic variants as biomarkers for progression and resistance in multiple myeloma

Cited by 6 publications

References 6 publications

Systematic discrimination of the repetitive genome in proximity of ferroptosis genes and a novel prognostic signature correlating with the oncogenic lncRNA CRNDE in multiple myeloma

Systematic discrimination of the repetitive genome in proximity of ferroptosis genes and a novel prognostic signature correlating with the oncogenic lncRNA CRNDE in multiple myeloma

Multiple Myeloma: Bioinformatic Analysis for Identification of Key Genes and Pathways

The Rationale for the Dual-Targeting Therapy for RSK2 and AKT in Multiple Myeloma

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