Decrypting Oncogenic Circuitry Through Translocation-Induced Enhancer Hijacking by TransFinder [CUT&Tag]

Here we introduce TransFinder, a multi-omics pipeline integrating SMRT-seq, Hi-C, RNA-seq, and CUT&Tag 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 translocations, t(5;8)(q35;q24) and t(1;22)(q25;q13), that activate MYC and CBX7 transcription, 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 events in other malignancies, including chronic myeloid leukemia (CML), where t(9;22)(q34;q11) repositioned an enhancer to activate BCR-ABL1 transcription, and pancreatic ductal adenocarcinoma (PDAC), where t(2;12)(p24;q24) hijacked an enhancer to ectopically activate SDC1.