A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia.
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.
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands; Department of Internal Medicine III, Ulm University Hospital, 89081 Ulm, Germany.
Stefan
S
Gröschel
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands.
Mathijs A
MA
Sanders
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands.
Remco
R
Hoogenboezem
Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, 3584 CT, the Netherlands.
Elzo
E
de Wit
Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, 3584 CT, the Netherlands.
Britta A M
BAM
Bouwman
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands.
Claudia
C
Erpelinck
Department of Immunology, Erasmus University Medical Center, Rotterdam, 3015 CN, the Netherlands.
Vincent H J
VHJ
van der Velden
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands.
Marije
M
Havermans
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands.
Roberto
R
Avellino
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands.
Kirsten
K
van Lom
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands.
Elwin J
EJ
Rombouts
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands.
Mark
M
van Duin
Department of Internal Medicine III, Ulm University Hospital, 89081 Ulm, Germany.
Konstanze
K
Döhner
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.
H Berna
HB
Beverloo
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
James E
JE
Bradner
Department of Internal Medicine III, Ulm University Hospital, 89081 Ulm, Germany.
Hartmut
H
Döhner
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands.
Bob
B
Löwenberg
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands.
Peter J M
PJM
Valk
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands.
Eric M J
EMJ
Bindels
Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, 3584 CT, the Netherlands.
Wouter
W
de Laat
Department of Hematology, Erasmus University Medical Center, Rotterdam, 3015 GE, the Netherlands. Electronic address: h.delwel@erasmusmc.nl.
Ruud
R
Delwel
D045744:Cell Line, Tumor; D007446:Chromosome Inversion; D002893:Chromosomes, Human, Pair 3; D004268:DNA-Binding Proteins / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D050989:GATA2 Transcription Factor / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D000074008:MDS1 and EVI1 Complex Locus Protein; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011519:Proto-Oncogenes / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors