Constitutive activation of alternative nuclear factor kappa B pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies

Seelig, Davis; Ito, Daisuke; Forster, Colleen L.; Yoon, Una Amelia; Breen, Matthew; Burns, Linda J.; Bachanová, Veronika; Lindblad‐Toh, Kerstin; O’Brien, Timothy; Schmechel, Stephen C.; Rizzardi, Anthony E.; Modiano, Jaime F.; Linden, Michael A.

doi:10.1080/10428194.2016.1260122

Cited by 10 publications

(9 citation statements)

References 30 publications

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“…Two different comparative gene expression studies 2 , 3 demonstrated that cDLBCL shares similar features with its human counterpart, in particular highlighting the interplay among specific molecular pathways (i.e. NF-κB, PI3K/AKT, Notch and JAK/STAT), which may have potential therapeutic implications 2 , 4 . In addition, recurrent copy number variations were identified by array comparative genomic hybridization (aCGH) including gains in chr13, syntenic to the region in human chromosome 8 containing MYC oncogene, and chr31 5 – 7 .…”

Section: Introductionmentioning

confidence: 99%

DNA methylation profiling reveals common signatures of tumorigenesis and defines epigenetic prognostic subtypes of canine Diffuse Large B-cell Lymphoma

Ferraresso

Aricò

Sanavia

et al. 2017

Sci Rep

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Epigenetic deregulation is a hallmark of cancer characterized by frequent acquisition of new DNA methylation in CpG islands. To gain insight into the methylation changes of canine DLBCL, we investigated the DNA methylome in primary DLBCLs in comparison with control lymph nodes by genome-wide CpG microarray. We identified 1,194 target loci showing different methylation levels in tumors compared with controls. The hypermethylated CpG loci included promoter, 5′-UTRs, upstream and exonic regions. Interestingly, targets of polycomb repressive complex in stem cells were mostly affected suggesting that DLBCL shares a stem cell-like epigenetic pattern. Functional analysis highlighted biological processes strongly related to embryonic development, tissue morphogenesis and cellular differentiation, including HOX, BMP and WNT. In addition, the analysis of epigenetic patterns and genome-wide methylation variability identified cDLBCL subgroups. Some of these epigenetic subtypes showed a concordance with the clinical outcome supporting the hypothesis that the accumulation of aberrant epigenetic changes results in a more aggressive behavior of the tumor. Collectively, our results suggest an important role of DNA methylation in DLBCL where aberrancies in transcription factors were frequently observed, suggesting an involvement during tumorigenesis. These findings warrant further investigation to improve cDLBCL prognostic classification and provide new insights on tumor aggressiveness.

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Section: Introductionmentioning

confidence: 99%

DNA methylation profiling reveals common signatures of tumorigenesis and defines epigenetic prognostic subtypes of canine Diffuse Large B-cell Lymphoma

Ferraresso

Aricò

Sanavia

et al. 2017

Sci Rep

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“…Many lymphoid malignancies, including human and canine DLBCL, have increased NF-kB signalling [ 3 , 79 , 80 ]. Recent molecular research has revealed that methylation of the CpG dinucleotide next to kB sites changes the regulatory activity of NF-kB [ 81 ].…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation-Mediated Silencing of CIDEA, MAL and PCDH17 Tumour Suppressor Genes in Canine DLBCL: From Multi-Omics Analyses to Mechanistic Studies

Zorzan

Elgendy

Guerra

et al. 2022

IJMS

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Gene expression is controlled by epigenetic deregulation, a hallmark of cancer. The DNA methylome of canine diffuse large B-cell lymphoma (cDLBCL), the most frequent malignancy of B-lymphocytes in dog, has recently been investigated, suggesting that aberrant hypermethylation of CpG loci is associated with gene silencing. Here, we used a multi-omics approach (DNA methylome, transcriptome and copy number variations) combined with functional in vitro assays, to identify putative tumour suppressor genes subjected to DNA methylation in cDLBCL. Using four cDLBCL primary cell cultures and CLBL-1 cells, we found that CiDEA, MAL and PCDH17, which were significantly suppressed in DLBCL samples, were hypermethylated and also responsive (at the DNA, mRNA and protein level) to pharmacological unmasking with hypomethylating drugs and histone deacetylase inhibitors. The regulatory mechanism underneath the methylation-dependent inhibition of those target genes expression was then investigated through luciferase and in vitro methylation assays. In the most responsive CpG-rich regions, an in silico analysis allowed the prediction of putative transcription factor binding sites influenced by DNA methylation. Interestingly, regulatory elements for AP2, MZF1, NF-kB, PAX5 and SP1 were commonly identified in all three genes. This study provides a foundation for characterisation and experimental validation of novel epigenetically-dysregulated pathways in cDLBCL.

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“…The molecular determinants for pevonedistat drug sensitivity may be beyond the scope of canonical NF‐κB signalling. Recent study showed that the alternative NF‐κB pathway (ANF‐κBP) is constitutively active in primary canine DLBCL samples, contributes to lymphoma cell survival and may serve as a therapeutic target . Thus, ANF‐κBP signalling status may also impact patient response to pevonedistat treatment.…”

Section: Discussionmentioning

confidence: 99%

Targeting NEDD8‐activating enzyme is a new approach to treat canine diffuse large B‐cell lymphoma

Assumpção

Marlowe

et al. 2018

Vet Comparative Oncology

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Canine diffuse large B-cell lymphoma (DLBCL), the most common hematologic malignancy of dogs, is associated with poor overall survival. The lack of conventional chemotherapies with sustainable efficacy warrants investigation of novel therapies. Pevonedistat (MLN4924) is a potent and selective small molecule NEDD8-activating enzyme inhibitor. In human activated B-cell-like (ABC) diffuse large B-cell lymphoma, pevonedistat induces lymphoma cell apoptosis, DNA damage and G1 cell cycle arrest by inhibiting the nuclear factor-κB (NF-κB) pathway. Genomic and transcriptomic studies showed that the NF-κB pathway is deregulated in canine DLBCL. Our results showed that pevonedistat treatment significantly reduces the viability of canine DLBCL cells by inducing G1 cell cycle arrest and apoptosis. Pevonedistat treatment inhibits NF-κB pathway activation and downregulates NF-κB target genes in canine DLBCL. Moreover, administration of pevonedistat to mice bearing canine DLBCL xenograft tumours resulted in tumour regression. Our in vivo and in vitro studies provide justification for future clinical application of pevonedistat as a potential new anti-cancer therapy that may benefit both canine and human species.

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Constitutive activation of alternative nuclear factor kappa B pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies

Cited by 10 publications

References 30 publications

DNA methylation profiling reveals common signatures of tumorigenesis and defines epigenetic prognostic subtypes of canine Diffuse Large B-cell Lymphoma

DNA methylation profiling reveals common signatures of tumorigenesis and defines epigenetic prognostic subtypes of canine Diffuse Large B-cell Lymphoma

Hypermethylation-Mediated Silencing of CIDEA, MAL and PCDH17 Tumour Suppressor Genes in Canine DLBCL: From Multi-Omics Analyses to Mechanistic Studies

Targeting NEDD8‐activating enzyme is a new approach to treat canine diffuse large B‐cell lymphoma

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