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Nat Commun. 2019 Jun 26;10(1):2789. doi: 10.1038/s41467-019-10637-8.

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

Author information

1
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
2
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
3
Pacific Biosciences, Menlo Park, CA, 94025, USA.
4
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
5
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. jinghui.zhang@stjude.org.

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.

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