Enhancer Extrachromosomal Circular DNA ANKRD28 Elicits Drug Resistance via POU2F2‐Mediated Transcriptional Network in Multiple Myeloma
Abstract Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes of both coding and non‐coding regions. However, the role of non‐coding...
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Wiley
2025-06-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202415695 |
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| author | Binzhen Chen Jia Liu Yaoxin Zhang Changming Shi Di Zhu Guoqiang Zhang Fei Xiao Lu Zhong Minyue Zhang Lai Guan Ng Honghui Huang Tingting Lu Jian Hou |
| author_facet | Binzhen Chen Jia Liu Yaoxin Zhang Changming Shi Di Zhu Guoqiang Zhang Fei Xiao Lu Zhong Minyue Zhang Lai Guan Ng Honghui Huang Tingting Lu Jian Hou |
| author_sort | Binzhen Chen |
| collection | DOAJ |
| description | Abstract Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes of both coding and non‐coding regions. However, the role of non‐coding eccDNA regions that serve as enhancers has been largely overlooked. Here, genome‐wide profiling of serum eccDNAs from donors and MM patients who responded well or poorly to bortezomib‐lenalidomide‐dexamethasone (VRd) therapy is characterized. A high copy number of eccDNA ANKRD28 (eccANKRD28) predicts poor therapy response and prognosis but enhanced transcriptional activity. Established VRd‐resistant MM cell lines exhibit a higher abundance of eccANKRD28, and CRISPR/Cas9‐mediated elevation of eccANKRD28 desensitizes bortezomib and lenalidomide treatment both in vitro and in vivo. Integrated multi‐omics analysis (H3K27ac ChIP‐seq, scRNA‐seq, scATAC‐seq, CUT&Tag, et al.) identifies eccANKRD28 as an active enhancer involved in drug resistance driven by the key transcription factor, POU class 2 homeobox 2 (POU2F2). POU2F2 interacts with sequence‐specific eccANKRD28 as well as RUNX1 and RUNX2 motifs to form the protein complex, which activates the promoter of oncogenes, including IRF4, JUNB, IKZF3, RUNX3, and BCL2. This study elucidates the potential transcriptional network of enhancer eccANKRD28 in MM drug resistance from a previously unrecognized epigenetic perspective. |
| format | Article |
| id | doaj-art-782c19a5a7954fe396b3c8de291f32fd |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-782c19a5a7954fe396b3c8de291f32fd2025-08-20T02:02:58ZengWileyAdvanced Science2198-38442025-06-011221n/an/a10.1002/advs.202415695Enhancer Extrachromosomal Circular DNA ANKRD28 Elicits Drug Resistance via POU2F2‐Mediated Transcriptional Network in Multiple MyelomaBinzhen Chen0Jia Liu1Yaoxin Zhang2Changming Shi3Di Zhu4Guoqiang Zhang5Fei Xiao6Lu Zhong7Minyue Zhang8Lai Guan Ng9Honghui Huang10Tingting Lu11Jian Hou12Department of HematologyRenji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127 ChinaDepartment of HematologyRenji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127 ChinaNational Center for Gene Research National Key Laboratory of Plant Molecular Genetics CAS Center for Excellence in Molecular Plant Sciences Institute of Plant Physiology and Ecology Chinese Academy of Sciences Shanghai 200032 ChinaShanghai Immune Therapy Institute Renji Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200127 ChinaDepartment of HematologyRenji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127 ChinaDepartment of HematologyRenji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127 ChinaDepartment of HematologyRenji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127 ChinaDepartment of HematologyRenji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127 ChinaDepartment of HematologyRenji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127 ChinaShanghai Immune Therapy Institute Renji Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200127 ChinaDepartment of HematologyRenji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127 ChinaSheng Yushou Center of Cell Biology and Immunology Department of Genetics and Developmental Science School of Life Sciences and Biotechnology Shanghai Jiao Tong University Shanghai 200240 ChinaDepartment of HematologyRenji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127 ChinaAbstract Multiple myeloma (MM) remains an incurable disease primarily due to the emergence of drug resistance, and the underlying mechanisms remain unclear. Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes of both coding and non‐coding regions. However, the role of non‐coding eccDNA regions that serve as enhancers has been largely overlooked. Here, genome‐wide profiling of serum eccDNAs from donors and MM patients who responded well or poorly to bortezomib‐lenalidomide‐dexamethasone (VRd) therapy is characterized. A high copy number of eccDNA ANKRD28 (eccANKRD28) predicts poor therapy response and prognosis but enhanced transcriptional activity. Established VRd‐resistant MM cell lines exhibit a higher abundance of eccANKRD28, and CRISPR/Cas9‐mediated elevation of eccANKRD28 desensitizes bortezomib and lenalidomide treatment both in vitro and in vivo. Integrated multi‐omics analysis (H3K27ac ChIP‐seq, scRNA‐seq, scATAC‐seq, CUT&Tag, et al.) identifies eccANKRD28 as an active enhancer involved in drug resistance driven by the key transcription factor, POU class 2 homeobox 2 (POU2F2). POU2F2 interacts with sequence‐specific eccANKRD28 as well as RUNX1 and RUNX2 motifs to form the protein complex, which activates the promoter of oncogenes, including IRF4, JUNB, IKZF3, RUNX3, and BCL2. This study elucidates the potential transcriptional network of enhancer eccANKRD28 in MM drug resistance from a previously unrecognized epigenetic perspective.https://doi.org/10.1002/advs.202415695multiple myelomaextrachromosomal circular DNAdrug resistanceenhancertranscriptional regulation |
| spellingShingle | Binzhen Chen Jia Liu Yaoxin Zhang Changming Shi Di Zhu Guoqiang Zhang Fei Xiao Lu Zhong Minyue Zhang Lai Guan Ng Honghui Huang Tingting Lu Jian Hou Enhancer Extrachromosomal Circular DNA ANKRD28 Elicits Drug Resistance via POU2F2‐Mediated Transcriptional Network in Multiple Myeloma Advanced Science multiple myeloma extrachromosomal circular DNA drug resistance enhancer transcriptional regulation |
| title | Enhancer Extrachromosomal Circular DNA ANKRD28 Elicits Drug Resistance via POU2F2‐Mediated Transcriptional Network in Multiple Myeloma |
| title_full | Enhancer Extrachromosomal Circular DNA ANKRD28 Elicits Drug Resistance via POU2F2‐Mediated Transcriptional Network in Multiple Myeloma |
| title_fullStr | Enhancer Extrachromosomal Circular DNA ANKRD28 Elicits Drug Resistance via POU2F2‐Mediated Transcriptional Network in Multiple Myeloma |
| title_full_unstemmed | Enhancer Extrachromosomal Circular DNA ANKRD28 Elicits Drug Resistance via POU2F2‐Mediated Transcriptional Network in Multiple Myeloma |
| title_short | Enhancer Extrachromosomal Circular DNA ANKRD28 Elicits Drug Resistance via POU2F2‐Mediated Transcriptional Network in Multiple Myeloma |
| title_sort | enhancer extrachromosomal circular dna ankrd28 elicits drug resistance via pou2f2 mediated transcriptional network in multiple myeloma |
| topic | multiple myeloma extrachromosomal circular DNA drug resistance enhancer transcriptional regulation |
| url | https://doi.org/10.1002/advs.202415695 |
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