B-ALL DUX4/ERG Subtype — St. Jude / Multi-institutional (2016)

Overview

A large multi-institutional cohort of 1,913 B-progenitor acute lymphoblastic leukemia (B-ALL) patients assembled at St. Jude Children’s Research Hospital with samples also from the Children’s Oncology Group, Alliance/CALGB, ECOG, and MD Anderson. The study was designed to characterize a newly discovered gene-expression cluster of B-ALL defined by IGH–DUX4 rearrangement and concurrent ERG deregulation. Genomic data are deposited at EGA accession EGAS00001000654 and dbGaP phs000463.v12.p5. PMID:27776115

Composition

  • 1,913 B-progenitor ALL patients: 1,347 children, 395 adolescents (age 16–20), 171 young adults (age 21–39). PMID:27776115
  • Cancer type: B-lymphoblastic leukemia/lymphoma (BLL).
  • 141/1,913 (7.6%) cases belonged to the DUX4/ERG subtype identified by the defining gene-expression cluster; comprising 5.2% of childhood standard-risk, 9.4% of childhood high-risk, 10.2% of adolescent, and 5.4% of adult B-ALL. PMID:27776115
  • Multi-protocol dataset spanning different treatment regimens across contributing institutions; heterogeneous clinical follow-up. PMID:27776115

Assays / panels (linked)

Papers using this cohort

  • PMID:27776115 — Zhang, Mullighan et al., Nat Genet 2016: Discovery and molecular characterization of the DUX4/ERG B-ALL subtype defined by IGH–DUX4 rearrangement and ERGalt isoform expression.

Notable findings derived from this cohort

  • IGH–DUX4 rearrangement is universal in all sequenced cases of this subtype; DUX4 is placed under the IGH enhancer with C-terminal truncation (e.g., E415, Q334) and read-through into the IGH locus. PMID:27776115
  • Focal ERG deletions in 55.6% (85/153) of subtype cases at 21q22.3 (most commonly exons 3–7 or 3–9 of NM_182918.3); breakpoints carry RAG recombination signal sequences, indicating RAG-mediated origin; not seen in other B-ALL or T-ALL. PMID:27776115
  • ERGalt, a novel 28 kDa C-terminal ERG isoform initiated from non-canonical exon 6 alt (located 197 nt proximal to ERG exon 7), detected by immunoblotting in 63.2% (50/79) tested cases; acts as a dominant-negative inhibitor of wild-type ERG; DUX4 directly binds the exon 6 alt promoter region (ChIP-seq confirmed). PMID:27776115
  • ERGalt is transforming: Arf−/− mouse hematopoietic cells transduced with ERGalt + NRAS G12D generate lymphoid-precursor, biphenotypic, or pre-B leukemias on transplantation. PMID:27776115
  • Mean 17.5 non-silent mutations per case (range 2–42); few structural alterations beyond the defining lesions; IKZF1 altered in 36.7%, PAX5 in 11.3%; Ras-pathway mutations in 35.2%; epigenetic modifiers (most commonly KMT2D, SETD2, ARID2, NCOR1) in 56.3%. PMID:27776115
  • Favorable prognosis despite IKZF1 loss: IKZF1 alterations (otherwise an adverse marker in B-ALL) did not confer poor outcome in this subtype, with direct implications for risk stratification. PMID:27776115
  • Subclonal-to-clonal ERG-deletion evolution demonstrated in xenografts and at relapse, supporting DUX4 rearrangement as the founding event preceding RAG-mediated ERG deletion. PMID:27776115

Sources

  • EGA accession: EGAS00001000654
  • dbGaP accession: phs000463.v12.p5
  • cBioPortal study ID: all_stjude_2016
  • Zhang, Mullighan et al., Nat Genet 2016 — DOI: 10.1038/ng.3691

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