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Cell. 2014 Apr 10;157(2):369-81. doi: 10.1016/j.cell.2014.02.019. Epub 2014 Apr 3.

A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia.

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  • 1Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands; Department of Internal Medicine III, Ulm University Hospital, 89081 Ulm, Germany.
  • 2Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands.
  • 3Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, 3584 CT, the Netherlands.
  • 4Department of Immunology, Erasmus University Medical Center, Rotterdam, 3015 CN, the Netherlands.
  • 5Department of Internal Medicine III, Ulm University Hospital, 89081 Ulm, Germany.
  • 6Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands; Dutch Working Group on Hemato-Oncologic Genome Diagnostics, Rotterdam, 3015 GE, the Netherlands.
  • 7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 8Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands. Electronic address: h.delwel@erasmusmc.nl.

Abstract

Chromosomal rearrangements without gene fusions have been implicated in leukemogenesis by causing deregulation of proto-oncogenes via relocation of cryptic regulatory DNA elements. AML with inv(3)/t(3;3) is associated with aberrant expression of the stem-cell regulator EVI1. Applying functional genomics and genome-engineering, we demonstrate that both 3q rearrangements reposition a distal GATA2 enhancer to ectopically activate EVI1 and simultaneously confer GATA2 functional haploinsufficiency, previously identified as the cause of sporadic familial AML/MDS and MonoMac/Emberger syndromes. Genomic excision of the ectopic enhancer restored EVI1 silencing and led to growth inhibition and differentiation of AML cells, which could be replicated by pharmacologic BET inhibition. Our data show that structural rearrangements involving the chromosomal repositioning of a single enhancer can cause deregulation of two unrelated distal genes, with cancer as the outcome.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24703711
[PubMed - indexed for MEDLINE]
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