Genome‐wide methylation analyses identify a subset of mantle cell lymphoma with a high number of methylated CpGs and aggressive clinicopathological features

Enjuanes, Anna; Albero, Robert; Clot, Guillem; Navarro, Alba; Beà, Sı́lvia; Pinyol, Magda; Martín‐Subero, José I.; Klapper, Wolfram; Staudt, Louis M.; Jaffe, Elaine S.; Rimsza, Lisa M.; Braziel, Rita M.; Delabie, Jan; Cook, James R.; Tubbs, Raymond R.; Gascoyne, Randy D.; Connors, Joseph M.; Weisenburger, Dennis D.; Greiner, Timothy C.; Chan, Wing C.; López‐Guillermo, Armando; Rosenwald, Andreas; Ott, German; Campo, Elı́as; Jares, Pedro

doi:10.1002/ijc.28321

Cited by 12 publications

(5 citation statements)

References 49 publications

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“…To test the hypothesis that SOX11 could play a relevant role in MCL tumor microenvironment interactions, we revisited our gene expression profiling and ChIP-chip data on MCL tumors. Reanalysis of differentially expressed genes by GSEA showed that SOX11 1 xenograft tumors 12 and primary MCLs, 24 compared with their SOX11 2 counterparts, were significantly enriched in cell migration and stromal stimulation signatures ( Figure 1A). Integrating GSEA data with SOX11-specific ChIP-chip data, 11 we found CXCR4 and PTK2 genes (encoding for FAK) to be the most significant SOX11-specific direct target genes within these tumor microenvironment pathways.…”

Section: Sox11 Directly Controls Cxcr4 and Ptk2 Gene Expression In MCLmentioning

confidence: 99%

SOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma

Balsas

Palomero

Eguileor

et al. 2017

Blood

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SOX11 overexpression in mantle cell lymphoma (MCL) has been associated with more aggressive behavior and worse outcome. However, SOX11 oncogenic pathways driving MCL tumor progression are poorly understood. Here, we demonstrate that SOX11 binds to regulatory regions of 2 important genes for microenvironment signals in cancer: (C-X-C motif) chemokine receptor 4 () and (encoding for focal adhesion kinase [FAK]). Moreover, SOX11 xenograft and human primary MCL tumors overexpress cell migration and stromal stimulation gene signatures compared with their SOX11 counterparts. We show that SOX11 directly upregulates CXCR4 and FAK expression, activating PI3K/AKT and ERK1/2 FAK-downstream pathways in MCL. Concordantly, SOX11 MCL cells have higher cell migration, transmigration through endothelial cells, adhesion to stromal cells, and cell proliferation and display an increased resistance to conventional drug therapies compared with SOX11 MCL cells. Specific FAK inhibition blocks downstream PI3K/AKT- and ERK1/2-mediated phosphorylation. Additionally, specific FAK and PI3K inhibitors reduce SOX11-enhanced MCL cell migration and stromal interactions and revert cell adhesion-mediated drug resistance (CAM-DR) to the same levels as SOX11 MCL cells. In intravenous MCL xenograft models, SOX11 MCL cells display higher cell migration, invasion, and growth compared with SOX11-knockdown cells, and specific FAK and CXCR4 inhibitors impair SOX11-enhanced MCL engraftment in bone marrow. Overall, our results suggest that SOX11 promotes MCL homing and invasion and increases CAM-DR through the direct regulation of CXCR4 and FAK expression and FAK/PI3K/AKT pathway activation, contributing to a more aggressive phenotype. Inhibition of this pathway may represent an efficient strategy to overcome stromal-mediated chemotherapy refractoriness in aggressive MCL.

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Section: Sox11 Directly Controls Cxcr4 and Ptk2 Gene Expression In MCLmentioning

confidence: 99%

SOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma

Balsas

Palomero

Eguileor

et al. 2017

Blood

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“…The DNA methylome of MCL remains largely unknown, as it has only been analyzed in promoter regions (Enjuanes et al, 2013; Halldorsdottir et al, 2012; Leshchenko et al, 2010; Rahmatpanah et al, 2006). To obtain deeper insights into MCL epigenetics, we have here we applied an analytic strategy to deconstruct the DNA methylome of MCL in the light of the complete normal B cell differentiation program (Kulis et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage

et al. 2016

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Summary We analyzed the in silico purified DNA methylation signatures of 82 mantle cell lymphomas (MCL) in comparison with cell subpopulations spanning the entire B cell lineage. We identified two MCL subgroups, respectively carrying epigenetic imprints of germinal center-inexperienced and germinal center-experienced B cells, and we found that DNA methylation profiles during lymphomagenesis are largely influenced by the methylation dynamics in normal B cells. An integrative epigenomic approach revealed 10,504 differentially methylated regions in regulatory elements marked by H3K27ac in MCL primary cases, including a distant enhancer showing de novo looping to the MCL oncogene SOX11. Finally, we observed that the magnitude of DNA methylation changes per case is highly variable and serves as an independent prognostic factor for MCL outcome.

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“…In malignant cells, hypermethylation at the CpG island induces suppression of numerousvital tumor suppressor genes, including p16 (25). Thus, small molecules targeting DNMTs may potentially reverse epigenetic silencing of cancer suppressor genes in a number of different cancer types.…”

Section: Epigenetic Modifications and Inhibitorsmentioning

confidence: 99%

Epigenetic actions of environmental factors and promising drugs for cancer therapy (Review)

Bai

Zhu

et al. 2017

Oncol Lett

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Abstract.Carcinogenesis is known to be primarily associa ted with gene mutations. Recently, increasing evidence has suggested that epigenetic events also serve crucial roles in tumor etiology. Environmental factors, including nutrition, toxicants and ethanol, are involved in carcinogenesis through inducing epigenetic modifications, such as DNA methylation, histone deacetylase and miRNA regulation. Studying epigenetic mechanisms has facilitated the development of early diagnostic strategies and potential therapeutic avenues. Modulation at the epigenetic level, including reversing epigenetic modifications using targeted drugs, has demonstrated promise in cancer therapy. Therefore, identifying novel epigenetic biomarkers and therapeutic targets has potential for the future of cancer therapy. The present review discusses the environmental factors involved in epigenetic modifications and potential drug candidates for cancer therapy.

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Genome‐wide methylation analyses identify a subset of mantle cell lymphoma with a high number of methylated CpGs and aggressive clinicopathological features

Cited by 12 publications

References 49 publications

SOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma

SOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma

Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage

Epigenetic actions of environmental factors and promising drugs for cancer therapy (Review)

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