Expression of integrin β-7 is epigenetically enhanced in multiple myeloma subgroups with high-risk cytogenetics
Abstract Background Oncogenic overexpression of integrin-β7 (ITGB7) in cases of high-risk multiple myeloma (MM) was reported to promote enhanced interactions between neoplastic plasma-B cells and stromal cells to develop cell-adhesion mediated drug resistance. Methods Expression profiles of adhesion...
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | Clinical Epigenetics |
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| Online Access: | https://doi.org/10.1186/s13148-023-01433-9 |
| _version_ | 1811171664335994880 |
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| author | Samrat Roy Choudhury Stephanie D. Byrum Duah Alkam Cody Ashby Fenghuang Zhan Alan J. Tackett Frits Van Rhee |
| author_facet | Samrat Roy Choudhury Stephanie D. Byrum Duah Alkam Cody Ashby Fenghuang Zhan Alan J. Tackett Frits Van Rhee |
| author_sort | Samrat Roy Choudhury |
| collection | DOAJ |
| description | Abstract Background Oncogenic overexpression of integrin-β7 (ITGB7) in cases of high-risk multiple myeloma (MM) was reported to promote enhanced interactions between neoplastic plasma-B cells and stromal cells to develop cell-adhesion mediated drug resistance. Methods Expression profiles of adhesion related genes were analyzed in a cohort of MM patients containing major IgH translocations or hyperdiploidies (HY), diagnosed at the premalignant monoclonal gammopathy of undetermined significance (MGUS; n = 103), smoldering multiple myeloma; (SMM; n = 190) or MM (MM; n = 53) stage. Differential expression was integrated with loci-specific alterations in DNA-methylation and chromatin marks in MM patients. A CRISPR-based targeted induction of DNA-methylation at the ITGB7 super-enhancer (SE) in MM.1S cells was employed to intersect the impact of cis-regulatory elements on ITGB7 expression. Results ITGB7 was significantly (p < 0.05) upregulated in patients with t(14;16) and t(14;20) subgroups in all MGUS, SMM and MM stages, but sporadically upregulated in t(4;14) subgroup at the MM stage. We demonstrate a predetermined enhancer state on ITGB7 in primary-B cells that is maintained under bivalent chromatin, which undergoes a process of chromatin-state alterations and develops into an active enhancer in cases of the t(4;14) subgroup or SE in cases of the t(14;16) subgroup. We also demonstrate that while targeted induction of DNA-methylation at the ITGB7-SE further upregulated the gene, inhibition of ITGB7-SE-associated transcription factor bromodomain-4 downregulated expression of the gene. Conclusions Our findings suggest an epigenetic regulation of oncogenic overexpression of ITGB7 in MM cells, which could be critical in MM progression and an attractive therapeutic target. |
| first_indexed | 2024-04-10T17:18:48Z |
| format | Article |
| id | doaj.art-da8930f7c5b643a592478ee5b0d59690 |
| institution | Directory Open Access Journal |
| issn | 1868-7083 |
| language | English |
| last_indexed | 2024-04-10T17:18:48Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj.art-da8930f7c5b643a592478ee5b0d596902023-02-05T12:16:20ZengBMCClinical Epigenetics1868-70832023-02-0115111410.1186/s13148-023-01433-9Expression of integrin β-7 is epigenetically enhanced in multiple myeloma subgroups with high-risk cytogeneticsSamrat Roy Choudhury0Stephanie D. Byrum1Duah Alkam2Cody Ashby3Fenghuang Zhan4Alan J. Tackett5Frits Van Rhee6Pediatric Hematology-Oncology, Arkansas Children’s Research Institute, University of Arkansas for Medical SciencesPediatric Hematology-Oncology, Arkansas Children’s Research Institute, University of Arkansas for Medical SciencesDepartment of Biochemistry and Molecular Biology, University of Arkansas for Medical SciencesDepartment of Biomedical Informatics, University of Arkansas for Medical SciencesMyeloma Center, Department of Internal Medicine, University of Arkansas for Medical SciencesPediatric Hematology-Oncology, Arkansas Children’s Research Institute, University of Arkansas for Medical SciencesMyeloma Center, Department of Internal Medicine, University of Arkansas for Medical SciencesAbstract Background Oncogenic overexpression of integrin-β7 (ITGB7) in cases of high-risk multiple myeloma (MM) was reported to promote enhanced interactions between neoplastic plasma-B cells and stromal cells to develop cell-adhesion mediated drug resistance. Methods Expression profiles of adhesion related genes were analyzed in a cohort of MM patients containing major IgH translocations or hyperdiploidies (HY), diagnosed at the premalignant monoclonal gammopathy of undetermined significance (MGUS; n = 103), smoldering multiple myeloma; (SMM; n = 190) or MM (MM; n = 53) stage. Differential expression was integrated with loci-specific alterations in DNA-methylation and chromatin marks in MM patients. A CRISPR-based targeted induction of DNA-methylation at the ITGB7 super-enhancer (SE) in MM.1S cells was employed to intersect the impact of cis-regulatory elements on ITGB7 expression. Results ITGB7 was significantly (p < 0.05) upregulated in patients with t(14;16) and t(14;20) subgroups in all MGUS, SMM and MM stages, but sporadically upregulated in t(4;14) subgroup at the MM stage. We demonstrate a predetermined enhancer state on ITGB7 in primary-B cells that is maintained under bivalent chromatin, which undergoes a process of chromatin-state alterations and develops into an active enhancer in cases of the t(4;14) subgroup or SE in cases of the t(14;16) subgroup. We also demonstrate that while targeted induction of DNA-methylation at the ITGB7-SE further upregulated the gene, inhibition of ITGB7-SE-associated transcription factor bromodomain-4 downregulated expression of the gene. Conclusions Our findings suggest an epigenetic regulation of oncogenic overexpression of ITGB7 in MM cells, which could be critical in MM progression and an attractive therapeutic target.https://doi.org/10.1186/s13148-023-01433-9Multiple myelomaITGB7T(14, 16) subgroupDNA methylationSuper-enhancerCRISPR |
| spellingShingle | Samrat Roy Choudhury Stephanie D. Byrum Duah Alkam Cody Ashby Fenghuang Zhan Alan J. Tackett Frits Van Rhee Expression of integrin β-7 is epigenetically enhanced in multiple myeloma subgroups with high-risk cytogenetics Clinical Epigenetics Multiple myeloma ITGB7 T(14, 16) subgroup DNA methylation Super-enhancer CRISPR |
| title | Expression of integrin β-7 is epigenetically enhanced in multiple myeloma subgroups with high-risk cytogenetics |
| title_full | Expression of integrin β-7 is epigenetically enhanced in multiple myeloma subgroups with high-risk cytogenetics |
| title_fullStr | Expression of integrin β-7 is epigenetically enhanced in multiple myeloma subgroups with high-risk cytogenetics |
| title_full_unstemmed | Expression of integrin β-7 is epigenetically enhanced in multiple myeloma subgroups with high-risk cytogenetics |
| title_short | Expression of integrin β-7 is epigenetically enhanced in multiple myeloma subgroups with high-risk cytogenetics |
| title_sort | expression of integrin β 7 is epigenetically enhanced in multiple myeloma subgroups with high risk cytogenetics |
| topic | Multiple myeloma ITGB7 T(14, 16) subgroup DNA methylation Super-enhancer CRISPR |
| url | https://doi.org/10.1186/s13148-023-01433-9 |
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