A Single Oncogenic Enhancer Rearrangement Causes Concomitant EVI1 and GATA2 Deregulation in Leukemia

被引:506
作者
Groeschel, Stefan [1 ,2 ]
Sanders, Mathijs A. [1 ]
Hoogenboezem, Remco [1 ]
de Wit, Elzo [3 ,4 ]
Bouwman, Britta A. M. [3 ,4 ]
Erpelinck, Claudia [1 ]
van der Velden, Vincent H. J. [5 ]
Havermans, Marije [1 ]
Avellino, Roberto [1 ]
van Lom, Kirsten [1 ]
Rombouts, Elwin J. [1 ]
van Duin, Mark [1 ]
Doehner, Konstanze [2 ]
Beverloo, H. Berna [6 ,7 ]
Bradner, James E. [8 ,9 ]
Doehner, Hartmut [2 ]
Lowenberg, Bob [1 ]
Valk, Peter J. M. [1 ]
Bindels, Eric M. J. [1 ]
de Laat, Wouter [3 ,4 ]
Delwel, Ruud [1 ]
机构
[1] Erasmus Univ, Med Ctr, Dept Hematol, NL-3015 GE Rotterdam, Netherlands
[2] Ulm Univ Hosp, Dept Internal Med 2, D-89081 Ulm, Germany
[3] Hubrecht Inst KNAW, NL-3584 CT Utrecht, Netherlands
[4] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands
[5] Erasmus Univ, Med Ctr, Dept Immunol, NL-3015 CN Rotterdam, Netherlands
[6] Erasmus Univ, Med Ctr, Dept Clin Genet, NL-3015 GE Rotterdam, Netherlands
[7] Dutch Working Grp Hematooncol Genome Diagnost, NL-3015 GE Rotterdam, Netherlands
[8] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[9] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA
关键词
HEMATOPOIETIC-CELLS; MUTATIONS; ACTIVATION; LOCUS; HAPLOINSUFFICIENCY; ABNORMALITIES; LANDSCAPE;
D O I
10.1016/j.cell.2014.02.019
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:369 / 381
页数:13
相关论文
共 35 条
[1]   CLONING THE CHROMOSOMAL BREAKPOINT OF T(14-18) HUMAN LYMPHOMAS - CLUSTERING AROUND JH ON CHROMOSOME-14 AND NEAR A TRANSCRIPTIONAL UNIT ON 18 [J].
BAKHSHI, A ;
JENSEN, JP ;
GOLDMAN, P ;
WRIGHT, JJ ;
MCBRIDE, OW ;
EPSTEIN, AL ;
KORSMEYER, SJ .
CELL, 1985, 41 (03) :899-906
[2]   Multiplex Genome Engineering Using CRISPR/Cas Systems [J].
Cong, Le ;
Ran, F. Ann ;
Cox, David ;
Lin, Shuailiang ;
Barretto, Robert ;
Habib, Naomi ;
Hsu, Patrick D. ;
Wu, Xuebing ;
Jiang, Wenyan ;
Marraffini, Luciano A. ;
Zhang, Feng .
SCIENCE, 2013, 339 (6121) :819-823
[3]   Gata2 is required for HSC generation and survival [J].
de Pater, Emma ;
Kaimakis, Polynikis ;
Vink, Chris S. ;
Yokomizo, Tomomasa ;
Yamada-Inagawa, Tomoko ;
van der Linden, Reinier ;
Kartalaei, Parham Solaimani ;
Camper, Sally A. ;
Speck, Nancy ;
Dzierzak, Elaine .
JOURNAL OF EXPERIMENTAL MEDICINE, 2013, 210 (13) :2843-2850
[4]   Controlling Long-Range Genomic Interactions at a Native Locus by Targeted Tethering of a Looping Factor [J].
Deng, Wulan ;
Lee, Jongjoo ;
Wang, Hongxin ;
Miller, Jeff ;
Reik, Andreas ;
Gregory, Philip D. ;
Dean, Ann ;
Blobel, Gerd A. .
CELL, 2012, 149 (06) :1233-1244
[5]   Topological domains in mammalian genomes identified by analysis of chromatin interactions [J].
Dixon, Jesse R. ;
Selvaraj, Siddarth ;
Yue, Feng ;
Kim, Audrey ;
Li, Yan ;
Shen, Yin ;
Hu, Ming ;
Liu, Jun S. ;
Ren, Bing .
NATURE, 2012, 485 (7398) :376-380
[6]   Chromosomal abnormalities in cancer [J].
Froehling, Stefan ;
Doehner, Hartmut .
NEW ENGLAND JOURNAL OF MEDICINE, 2008, 359 (07) :722-734
[7]   Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells [J].
Goyama, Susumu ;
Yamamoto, Go ;
Shimabe, Munetake ;
Sato, Tomohiko ;
Ichikawa, Motoshi ;
Ogawa, Seishi ;
Chiba, Shigeru ;
Kurokawa, Mineo .
CELL STEM CELL, 2008, 3 (02) :207-220
[8]   Distinct functions of dispersed GATA factor complexes at an endogenous gene locus [J].
Grass, Jeffrey A. ;
Jing, Huie ;
Kim, Shin-Il ;
Martowicz, Melissa L. ;
Pal, Saumen ;
Blobel, Gerd A. ;
Bresnick, Emery H. .
MOLECULAR AND CELLULAR BIOLOGY, 2006, 26 (19) :7056-7067
[9]   Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia [J].
Hahn, Christopher N. ;
Chong, Chan-Eng ;
Carmichael, Catherine L. ;
Wilkins, Ella J. ;
Brautigan, Peter J. ;
Li, Xiao-Chun ;
Babic, Milena ;
Lin, Ming ;
Carmagnac, Amandine ;
Lee, Young K. ;
Kok, Chung H. ;
Gagliardi, Lucia ;
Friend, Kathryn L. ;
Ekert, Paul G. ;
Butcher, Carolyn M. ;
Brown, Anna L. ;
Lewis, Ian D. ;
To, L. Bik ;
Timms, Andrew E. ;
Storek, Jan ;
Moore, Sarah ;
Altree, Meryl ;
Escher, Robert ;
Bardy, Peter G. ;
Suthers, Graeme K. ;
D'Andrea, Richard J. ;
Horwitz, Marshall S. ;
Scott, Hamish S. .
NATURE GENETICS, 2011, 43 (10) :1012-U130
[10]   GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome [J].
Hsu, Amy P. ;
Johnson, Kirby D. ;
Falcone, E. Liana ;
Sanalkumar, Rajendran ;
Sanchez, Lauren ;
Hickstein, Dennis D. ;
Cuellar-Rodriguez, Jennifer ;
Lemieux, Jacob E. ;
Zerbe, Christa S. ;
Bresnick, Emery H. ;
Holland, Steven M. .
BLOOD, 2013, 121 (19) :3830-3837