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Peer-reviewedCC BYScience Advances

Translocation-induced enhancer rewiring reveals cryptic oncogenic circuits in multiple myeloma

  • Enrun Zheng1
  • Qinghua Li1
  • Xuelin Dou2
  • Yiping Cao1
  • Chao Ren3
  • Feiya Suo1
  • Lin Lin3
  • Yan Zhao1,4
  • Zhiwei Liao1
  • Yang Liu2
  • Zesen Shang5
  • Sudun Guan1
15 more authors
  • Chengying Zhang1
  • Mengyu Yang1
  • Pengyu Xiang1
  • Yakun Chen6
  • Xinhua Liu7
  • Yueyun Lai2
  • Zhiqiang Liu8
  • Adkhamjon Odilovich Abdullayev9
  • Lin He1,4
  • Xiaochen Bo3
  • Yongfeng Shang1
  • Jichuan Wang10
  • Jin Lu2
  • Hebing Chen3
  • Luyang Sun1,11
11 affiliations
  1. 1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China.
  2. 2Peking University Institute of Hematology, Collaborative Innovation Center of Hematology, Peking University People’s Hospital, Beijing 100044, China.
  3. 3Academy of Military Medical Sciences, Beijing 100850, China.
  4. 4Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  5. 5Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China.
  6. 6Beijing Genome Precision Technology Co. Ltd., Beijing 100176, China.
  7. 7Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China.
  8. 8Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China.
  9. 9Laboratory of Molecular Genetics, Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of Uzbekistan, Tashkent 100109, Uzbekistan.
  10. 10Musculoskeletal Tumor Center, Beijing Key Laboratory for Musculoskeletal Tumors, Peking University People’s Hospital, Beijing 100037, China.
  11. 11Department of Hematology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan 030032, China.
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Abstract

Immunoglobulin heavy chain ( IGH ) enhancer translocations drive multiple myeloma (MM), but routine diagnostics resolve only 32 to 38% of cases. Here, we introduce TransFinder, a multiomic pipeline integrating SMRT long-read sequencing (LRS), Hi-C, H3K27ac ChIP-seq/CUT&Tag, and RNA-seq to systematically resolve cryptic translocations and their hijacked oncogenes by deconvoluting enhancer-promoter neo-loops at rearrangement breakpoints. Applied to MM, TransFinder identified that t(16;22)(q23;q11), a canonical translocation known to activate MAF , also hijacks enhancers to activate RAB36 . It further uncovered previously unrecognized t(5;8)(q35;q24) and t(1;22)(q25;q13), which activate MYC and CBX7 , respectively, through chromatin topology rewiring. CRISPR-Cas9–engineered t(1;22)(q25;q13) recapitulated CBX7 induction, and pharmacological inhibition of CBX7 suppressed myeloma cell proliferation. Beyond MM, TransFinder identified enhancer hijacking in chronic myeloid leukemia, where t(9;22)(q34;q11) repositioned an enhancer to activate BCR-ABL1 , and pancreatic ductal adenocarcinoma, where t(2;12)(p24;q24) hijacked an enhancer to activate SDC1 . Linking 3D genome architecture to oncogene activation, TransFinder decodes oncogenic structural variants and their trans-activities, establishing clinically actionable dependencies of noncoding drivers in malignancies.

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Cite

BibTeXRIS
BibTeX
@article{zheng2026translocationinduced,
  title = {{Translocation-induced enhancer rewiring reveals cryptic oncogenic circuits in multiple myeloma}},
  author = {Enrun Zheng and Qinghua Li and Xuelin Dou and Yiping Cao and Chao Ren and Feiya Suo and Lin Lin and Yan Zhao and Zhiwei Liao and Yang Liu and Zesen Shang and Sudun Guan and Chengying Zhang and Mengyu Yang and Pengyu Xiang and Yakun Chen and Xinhua Liu and Yueyun Lai and Zhiqiang Liu and Adkhamjon Odilovich Abdullayev and Lin He and Xiaochen Bo and Yongfeng Shang and Jichuan Wang and Jin Lu and Hebing Chen and Luyang Sun},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeg9610},
  url = {https://www.science.org/doi/10.1126/sciadv.aeg9610},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Translocation-induced enhancer rewiring reveals cryptic oncogenic circuits in multiple myeloma
AU  - Enrun Zheng
AU  - Qinghua Li
AU  - Xuelin Dou
AU  - Yiping Cao
AU  - Chao Ren
AU  - Feiya Suo
AU  - Lin Lin
AU  - Yan Zhao
AU  - Zhiwei Liao
AU  - Yang Liu
AU  - Zesen Shang
AU  - Sudun Guan
AU  - Chengying Zhang
AU  - Mengyu Yang
AU  - Pengyu Xiang
AU  - Yakun Chen
AU  - Xinhua Liu
AU  - Yueyun Lai
AU  - Zhiqiang Liu
AU  - Adkhamjon Odilovich Abdullayev
AU  - Lin He
AU  - Xiaochen Bo
AU  - Yongfeng Shang
AU  - Jichuan Wang
AU  - Jin Lu
AU  - Hebing Chen
AU  - Luyang Sun
PY  - 2026
DA  - 2026/10/09
JO  - Science Advances
DO  - 10.1126/sciadv.aeg9610
UR  - https://www.science.org/doi/10.1126/sciadv.aeg9610
AB  - Immunoglobulin heavy chain ( IGH ) enhancer translocations drive multiple myeloma (MM), but routine diagnostics resolve only 32 to 38% of cases. Here, we introduce TransFinder, a multiomic pipeline integrating SMRT long-read sequencing (LRS), Hi-C, H3K27ac ChIP-seq/CUT&Tag, and RNA-seq to systematically resolve cryptic translocations and their hijacked oncogenes by deconvoluting enhancer-promoter neo-loops at rearrangement breakpoints. Applied to MM, TransFinder identified that t(16;22)(q23;q11), a canonical translocation known to activate MAF , also hijacks enhancers to activate RAB36 . It further uncovered previously unrecognized t(5;8)(q35;q24) and t(1;22)(q25;q13), which activate MYC and CBX7 , respectively, through chromatin topology rewiring. CRISPR-Cas9–engineered t(1;22)(q25;q13) recapitulated CBX7 induction, and pharmacological inhibition of CBX7 suppressed myeloma cell proliferation. Beyond MM, TransFinder identified enhancer hijacking in chronic myeloid leukemia, where t(9;22)(q34;q11) repositioned an enhancer to activate BCR-ABL1 , and pancreatic ductal adenocarcinoma, where t(2;12)(p24;q24) hijacked an enhancer to activate SDC1 . Linking 3D genome architecture to oncogene activation, TransFinder decodes oncogenic structural variants and their trans-activities, establishing clinically actionable dependencies of noncoding drivers in malignancies.
SN  - 2375-2548
ER  -