Translocation-induced enhancer rewiring reveals cryptic oncogenic circuits in multiple myeloma
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.
Authors
- Chengying Zhang (ORCID: https://orcid.org/0009-0000-4173-0753)
- Jin Lu (ORCID: https://orcid.org/0000-0001-5004-2741)
- Sudun Guan
- Yiping Cao (ORCID: https://orcid.org/0000-0001-9218-8095)
- Qinghua Li (ORCID: https://orcid.org/0009-0003-1955-701X)
- А О Абдуллаев (ORCID: https://orcid.org/0000-0003-2530-808X)
- Xinhua Liu (ORCID: https://orcid.org/0000-0002-7984-2977)
- Hebing Chen (ORCID: https://orcid.org/0000-0003-4102-356X)
- 赖悦云
- Jichuan Wang (ORCID: https://orcid.org/0009-0005-7194-0192)
- Zesen Shang
- Enrun Zheng (ORCID: https://orcid.org/0009-0004-4547-7336)
- Luyang Sun (ORCID: https://orcid.org/0000-0003-3917-473X)
- Zhiwei Liao (ORCID: https://orcid.org/0000-0001-6643-9495)
- Zhiqiang Liu (ORCID: https://orcid.org/0000-0002-0677-8097)
- Lin He (ORCID: https://orcid.org/0000-0001-7429-8012)
- Lin Lin (ORCID: https://orcid.org/0009-0006-8310-9010)
- Xiaochen Bo (ORCID: https://orcid.org/0000-0003-3490-5812)
- Pengyu Xiang (ORCID: https://orcid.org/0009-0005-7497-5649)
- Mengyu Yang (ORCID: https://orcid.org/0009-0002-7837-1015)
- Yang Liu (ORCID: https://orcid.org/0000-0002-8471-8460)
- Xuelin Dou (ORCID: https://orcid.org/0000-0001-7040-9272)
- Yakun Chen
- Yongfeng Shang (ORCID: https://orcid.org/0000-0001-5050-7625)
- Yan Zhao
- Chao Ren
- Feiya Suo
Institutions
- Hangzhou Normal University (CN)
- Peking University (CN)
- Academy of Military Medical Sciences (CN)
- Shandong Tumor Hospital (CN)
- Peking University People's Hospital (CN)
- Peking University Third Hospital (CN)
- Shanxi Academy of Medical Sciences (CN)
- Tashkent Pediatric Medical Institute (UZ)
- Shandong First Medical University (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2026-10-07
- DOI
- https://doi.org/10.1126/sciadv.aeg9610
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00