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.
Highlights
IGH@ proto-oncogene translocation is a common oncogenic event in lymphoid lineage cancers such as B-cell acute lymphoblastic leukemia (B-ALL), lymphoma and multiple myeloma
Using published RNA-seq data generated from 32 B-ALL patient samples that harboring IGH-DUX4 translocation and human embryos[9,13,17], we found that DUX4 expression is much higher compared with normal expression in human cleavage stage embryos
B-cell development initiates from hematopoietic stem cells with both IGH alleles hypo-acetylated and silenced by DNA hypermethylation[1,18]. This is followed by the development of early progenitor B cells where both IGH alleles undergo D-to-J rearrangement
Summary
IGH@ proto-oncogene translocation is a common oncogenic event in lymphoid lineage cancers such as B-ALL, lymphoma and multiple myeloma. 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 Nalm[6], 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 IGHDUX4 translocation occurs on the silenced IGH allele. In vitro, this reduces the oncogenic stress of DUX4 high-level expression. Significant allelic imbalance is detected on the wild type over the IGH-DUX4 haplotype, showing that IGHDUX4 translocation occurs on the silenced IGH allele. Patient samples of IGH-DUX4 B-ALL have similar expression profiles and IGH breakpoints as Nalm[6], suggesting this could be a common mechanism; further analyses of haplotype structure and epigenetic profiling are required
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