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

Stefan Gröschel; Mathijs A Sanders; Remco Hoogenboezem; Elzo de Wit; Britta A M Bouwman; Claudia Erpelinck; Vincent H J van der Velden; Marije Havermans; Roberto Avellino; Kirsten van Lom; Elwin J Rombouts; Mark van Duin; Konstanze Döhner; H Berna Beverloo; James E Bradner; Hartmut Döhner; Bob Löwenberg; Peter J M Valk; Eric M J Bindels; Wouter de Laat; Ruud Delwel

doi:10.1016/j.cell.2014.02.019

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

Cell. 2014 Apr 10;157(2):369-381. doi: 10.1016/j.cell.2014.02.019. Epub 2014 Apr 3.

Authors

Stefan Gröschel¹, Mathijs A Sanders², Remco Hoogenboezem², Elzo de Wit³, Britta A M Bouwman³, Claudia Erpelinck², Vincent H J van der Velden⁴, Marije Havermans², Roberto Avellino², Kirsten van Lom², Elwin J Rombouts², Mark van Duin², Konstanze Döhner⁵, H Berna Beverloo⁶, James E Bradner⁷, Hartmut Döhner⁵, Bob Löwenberg², Peter J M Valk², Eric M J Bindels², Wouter de Laat³, Ruud Delwel⁸

Affiliations

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

PMID: 24703711
DOI: 10.1016/j.cell.2014.02.019

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Chromosome Inversion
Chromosomes, Human, Pair 3*
DNA-Binding Proteins / genetics*
Enhancer Elements, Genetic*
GATA2 Transcription Factor / genetics*
Gene Expression Regulation, Neoplastic*
Humans
Leukemia, Myeloid, Acute / genetics*
MDS1 and EVI1 Complex Locus Protein
Myelodysplastic Syndromes / genetics*
Promoter Regions, Genetic
Proto-Oncogenes / genetics*
Transcription Factors / genetics*
Transcriptional Activation
Translocation, Genetic

Substances

DNA-Binding Proteins
GATA2 Transcription Factor
MDS1 and EVI1 Complex Locus Protein
MECOM protein, human
Transcription Factors

Grants and funding

12-1309/AICR_/Worldwide Cancer Research/United Kingdom