Science advances · 2026
Translocation-induced enhancer rewiring reveals cryptic oncogenic circuits in multiple myeloma.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Zheng Enrun, Li Qinghua, Dou Xuelin, Cao Yiping, Ren Chao, Suo Feiya, Lin Lin, Zhao Yan, Liao Zhiwei, Liu Yang, Shang Zesen, Guan Sudun, Zhang Chengying, Yang Mengyu, Xiang Pengyu, Chen Yakun, Liu Xinhua, Lai Yueyun, Liu Zhiqiang, Abdullayev Adkhamjon Odilovich, He Lin, Bo Xiaochen, Shang Yongfeng, Wang Jichuan, Lu Jin, Chen Hebing, Sun Luyang
Аннотация
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.