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

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 LaatRuud Delwel

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

503 Citations (Scopus)

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.

Original language	English
Pages (from-to)	369-81
Number of pages	13
Journal	Cell
Volume	157
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2014.02.019
Publication status	Published - 10 Apr 2014

Keywords

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

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Gröschel, S., Sanders, M. A., Hoogenboezem, R., de Wit, E., Bouwman, B. A. M., Erpelinck, C., van der Velden, V. H. J., Havermans, M., Avellino, R., van Lom, K., Rombouts, E. J., van Duin, M., Döhner, K., Beverloo, H. B., Bradner, J. E., Döhner, H., Löwenberg, B., Valk, P. J. M., Bindels, E. M. J., ... Delwel, R. (2014). A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell, 157(2), 369-81. https://doi.org/10.1016/j.cell.2014.02.019

@article{2665564cef2543e09b41ace5880286d2,

title = "A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia",

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.",

keywords = "Cell Line, Tumor, Chromosome Inversion, Chromosomes, Human, Pair 3, DNA-Binding Proteins, Enhancer Elements, Genetic, GATA2 Transcription Factor, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Promoter Regions, Genetic, Proto-Oncogenes, Transcription Factors, Transcriptional Activation, Translocation, Genetic",

author = "Stefan Gr{\"o}schel and Sanders, {Mathijs A} and Remco Hoogenboezem and {de Wit}, Elzo and Bouwman, {Britta A M} and Claudia Erpelinck and {van der Velden}, {Vincent H J} and Marije Havermans and Roberto Avellino and {van Lom}, Kirsten and Rombouts, {Elwin J} and {van Duin}, Mark and Konstanze D{\"o}hner and Beverloo, {H Berna} and Bradner, {James E} and Hartmut D{\"o}hner and Bob L{\"o}wenberg and Valk, {Peter J M} and Bindels, {Eric M J} and {de Laat}, Wouter and Ruud Delwel",

year = "2014",

month = apr,

day = "10",

doi = "10.1016/j.cell.2014.02.019",

language = "English",

volume = "157",

pages = "369--81",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "2",

}

Gröschel, S, Sanders, MA, Hoogenboezem, R, de Wit, E, Bouwman, BAM, Erpelinck, C, van der Velden, VHJ, Havermans, M, Avellino, R, van Lom, K, Rombouts, EJ, van Duin, M, Döhner, K, Beverloo, HB, Bradner, JE, Döhner, H, Löwenberg, B, Valk, PJM, Bindels, EMJ, de Laat, W & Delwel, R 2014, 'A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia', Cell, vol. 157, no. 2, pp. 369-81. https://doi.org/10.1016/j.cell.2014.02.019

TY - JOUR

T1 - A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia

AU - Gröschel, Stefan

AU - Sanders, Mathijs A

AU - Hoogenboezem, Remco

AU - de Wit, Elzo

AU - Bouwman, Britta A M

AU - Erpelinck, Claudia

AU - van der Velden, Vincent H J

AU - Havermans, Marije

AU - Avellino, Roberto

AU - van Lom, Kirsten

AU - Rombouts, Elwin J

AU - van Duin, Mark

AU - Döhner, Konstanze

AU - Beverloo, H Berna

AU - Bradner, James E

AU - Döhner, Hartmut

AU - Löwenberg, Bob

AU - Valk, Peter J M

AU - Bindels, Eric M J

AU - de Laat, Wouter

AU - Delwel, Ruud

PY - 2014/4/10

Y1 - 2014/4/10

N2 - 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.

AB - 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.

KW - Cell Line, Tumor

KW - Chromosome Inversion

KW - Chromosomes, Human, Pair 3

KW - DNA-Binding Proteins

KW - Enhancer Elements, Genetic

KW - GATA2 Transcription Factor

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Leukemia, Myeloid, Acute

KW - Myelodysplastic Syndromes

KW - Promoter Regions, Genetic

KW - Proto-Oncogenes

KW - Transcription Factors

KW - Transcriptional Activation

KW - Translocation, Genetic

U2 - 10.1016/j.cell.2014.02.019

DO - 10.1016/j.cell.2014.02.019

M3 - Article

C2 - 24703711

SN - 0092-8674

VL - 157

SP - 369

EP - 381

JO - Cell

JF - Cell

IS - 2

ER -

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

Abstract

Keywords

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