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

Liqing Tian, Ying Shao, Stephanie Nance, Jinjun Dang, Beisi Xu, Xiaotu Ma, Yongjin Li, Bensheng Ju, Li Dong, Scott Newman, Xin Zhou, Patrick Schreiner, Elizabeth Tseng, Ting Hon, Meredith Ashby, Chunliang Li, John Easton, Tanja A. Gruber and Jinghui Zhang ()
Additional contact information
Liqing Tian: St. Jude Children’s Research Hospital
Ying Shao: St. Jude Children’s Research Hospital
Stephanie Nance: St. Jude Children’s Research Hospital
Jinjun Dang: St. Jude Children’s Research Hospital
Beisi Xu: St. Jude Children’s Research Hospital
Xiaotu Ma: St. Jude Children’s Research Hospital
Yongjin Li: St. Jude Children’s Research Hospital
Bensheng Ju: St. Jude Children’s Research Hospital
Li Dong: St. Jude Children’s Research Hospital
Scott Newman: St. Jude Children’s Research Hospital
Xin Zhou: St. Jude Children’s Research Hospital
Patrick Schreiner: St. Jude Children’s Research Hospital
Elizabeth Tseng: Pacific Biosciences
Ting Hon: Pacific Biosciences
Meredith Ashby: Pacific Biosciences
Chunliang Li: St. Jude Children’s Research Hospital
John Easton: St. Jude Children’s Research Hospital
Tanja A. Gruber: St. Jude Children’s Research Hospital
Jinghui Zhang: St. Jude Children’s Research Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10637-8

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