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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • DNA / genetics
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Genomics
  • Histones
  • Homeodomain Proteins / metabolism*
  • Humans
  • Immunoglobulin Heavy Chains / metabolism*
  • Mice
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Whole Genome Sequencing

Substances

  • DUX4L1 protein, human
  • Histones
  • Homeodomain Proteins
  • Immunoglobulin Heavy Chains
  • DNA