Long-read sequencing unveils IGH-DUX4 translocation into the silenced IGH allele in B-cell acute lymphoblastic leukemia.

Authors: Tian, Liqing and Shao, Ying and Nance, Stephanie and Dang, Jinjun and Xu, Beisi and Ma, Xiaotu and Li, Yongjin and Ju, Bensheng and Dong, Li and Newman, Scott and Zhou, Xin and Schreiner, Patrick and Tseng, Elizabeth and Hon, Ting and Ashby, Meredith and Li, Chunliang and Easton, John and Gruber, Tanja A and Zhang, Jinghui

IGH@ proto-oncogene translocation is a common oncogenic event in lymphoid lineage cancers such as B-ALL, lymphoma and multiple myeloma. Here, to investigate the interplay between IGH@ proto-oncogene translocation and IGH allelic exclusion, we perform long-read whole-genome and transcriptome sequencing along with epigenetic and 3D genome profiling of Nalm6, an IGH-DUX4 positive B-ALL cell line. We detect significant allelic imbalance on the wild-type over the IGH-DUX4 haplotype in expression and epigenetic data, showing IGH-DUX4 translocation occurs on the silenced IGH allele. In vitro, this reduces the oncogenic stress of DUX4 high-level expression. Moreover, patient samples of IGH-DUX4 B-ALL have similar expression profile and IGH breakpoints as Nalm6, suggesting a common mechanism to allow optimal dosage of non-toxic DUX4 expression.

Journal: Nature communications
DOI: 10.1038/s41467-019-10637-8
Year: 2019

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