Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome)
Pia Ostergaard,Michael A. Simpson,Fiona Connell,Colin G. Steward,Glen Brice,Wesley J. Woollard,Dimitra Dafou,Tatjana Kilo,Sarah F. Smithson,Peter Lunt,Victoria Murday,Shirley Hodgson,Russell Keenan,Daniela T. Pilz,Ines Martinez-Corral,Taija Makinen,Peter S. Mortimer,Steve Jeffery,Richard C. Trembath,Sahar Mansour +19 more
TLDR
It is indicated that haploinsufficiency of GATA2 underlies primary lymphedema and predisposes to acute myeloid leukemia in Emberger syndrome.Abstract:
We report an allelic series of eight mutations in GATA2 underlying Emberger syndrome, an autosomal dominant primary lymphedema associated with a predisposition to acute myeloid leukemia. GATA2 is a transcription factor that plays an essential role in gene regulation during vascular development and hematopoietic differentiation. Our findings indicate that haploinsufficiency of GATA2 underlies primary lymphedema and predisposes to acute myeloid leukemia in this syndrome.read more
Citations
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Journal ArticleDOI
The lymphatic vasculature in disease
TL;DR: This review highlights the most recent developments in lymphatic biology and how the lymphatic system contributes to the pathogenesis of various diseases involving immune and inflammatory responses and its role in disseminating tumor cells.
Journal ArticleDOI
GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics and immunity
Michael A. Spinner,Lauren A. Sanchez,Amy P. Hsu,Pamela A. Shaw,Christa S. Zerbe,Katherine R. Calvo,Diane C. Arthur,Wenjuan Gu,Christine M. Gould,Carmen C. Brewer,Edward W. Cowen,Alexandra F. Freeman,Kenneth N. Olivier,Gulbu Uzel,Adrian M. Zelazny,Janine Daub,Christine Spalding,Reginald J. Claypool,Neelam Giri,Blanche P. Alter,Emily M. Mace,Jordan S. Orange,Jennifer Cuellar-Rodriguez,Dennis D. Hickstein,Steven M. Holland +24 more
TL;DR: GATA2 deficiency unites susceptibility to MDS/AML, immunodeficiency, pulmonary disease, and vascular/lymphatic dysfunction, and monocytopenia, B, NK, and CD4 lymphocy topenia correlated with the presence of disease.
Journal ArticleDOI
A Single Oncogenic Enhancer Rearrangement Causes Concomitant EVI1 and GATA2 Deregulation in Leukemia
Stefan Gröschel,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. C. 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 +21 more
TL;DR: The 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.
Journal ArticleDOI
A robust model for read count data in exome sequencing experiments and implications for copy number variant calling
Vincent Plagnol,James Curtis,Michael Epstein,Kin Y. Mok,Emma Stebbings,Sofia Grigoriadou,Nicholas W. Wood,Sophie Hambleton,Siobhan O. Burns,Adrian J. Thrasher,Dinakantha S. Kumararatne,Rainer Doffinger,Sergey Nejentsev +12 more
TL;DR: This analysis identified two novel causative deletions in the genes GATA2 and DOCK8 and introduced ExomeDepth, a new CNV calling algorithm designed to control for technical variability between samples in exome sequence data.
Journal ArticleDOI
Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia
Christopher N. Hahn,Christopher N. Hahn,Chan-Eng Chong,Chan-Eng Chong,Catherine Carmichael,Ella J Wilkins,Ella J Wilkins,Peter J. Brautigan,Xiaochun Li,Milena Babic,Ming-Chih Lin,Amandine Carmagnac,Young Koung Lee,Chung H. Kok,Lucia Gagliardi,Kathryn Friend,Paul G Ekert,Carolyn M. Butcher,Anna L. Brown,Ian D. Lewis,Ian D. Lewis,L. Bik To,L. Bik To,Andrew E. Timms,Jan Storek,Sarah Moore,Meryl Altree,Robert Escher,Robert Escher,Peter Bardy,Graeme Suthers,Graeme Suthers,Richard J D'Andrea,Richard J D'Andrea,Marshall S. Horwitz,Hamish S. Scott +35 more
TL;DR: The discovery of GATA2 as a new myelodysplastic syndrome (MDS)-acute myeloid leukemia (AML) predisposition gene is reported and differential effects of the mutations on the transactivation of target genes, cellular differentiation, apoptosis and global gene expression are shown.
References
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Journal ArticleDOI
An early haematopoietic defect in mice lacking the transcription factor GATA-2.
Fong-Ying Tsai,Fong-Ying Tsai,Gordon Keller,Frank C. Kuo,Mitchell J. Weiss,Jianzhou Chen,Margery Rosenblatt,Frederick W. Alt,Stuart H. Orkin,Stuart H. Orkin +9 more
TL;DR: It is demonstrated that the transcription factor GATA-2 plays a critical role in haematopoiesis, particularly of an adult type, and proposed that it regulates genes controlling growth factor responsiveness or the proliferative capacity of early haem atopoietic cells.
Journal ArticleDOI
Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia
W.-J. Song,M. G. Sullivan,R. D. Legare,S Hutchings,Xiaolian Tan,Dubravka Kufrin,Janina Ratajczak,I. C. Resende,C. Haworth,R. Hock,Mignon L. Loh,C. Felix,Denis-Claude Roy,Lambert Busque,David M. Kurnit,Cheryl L. Willman,Alan M. Gewirtz,Nancy A. Speck,John H. Bushweller,Fugen Li,K. Gardiner,Mortimer Poncz,John M. Maris,D. G. Gilliland,D. G. Gilliland +24 more
TL;DR: The findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.
Journal ArticleDOI
Dominant-negative mutations of CEBPA , encoding CCAAT/enhancer binding protein-α (C/EBPα), in acute myeloid leukemia
Thomas Pabst,Beatrice U. Mueller,Pu Zhang,Hanna S. Radomska,Sailaja Narravula,Susanne Schnittger,Gerhard Behre,Wolfgang Hiddemann,Daniel G. Tenen +8 more
TL;DR: This is the first report of CEBPA mutations in human neoplasia, and such mutations are likely to induce the differentiation block found in AML.
Journal ArticleDOI
Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome
Amy P. Hsu,Elizabeth P. Sampaio,Javed Khan,Katherine R. Calvo,Jacob E. Lemieux,Smita Y. Patel,David M. Frucht,Donald C. Vinh,Roger D. Auth,Alexandra F. Freeman,Kenneth N. Olivier,Gulbu Uzel,Christa S. Zerbe,Christine Spalding,Stefania Pittaluga,Mark Raffeld,Douglas B. Kuhns,Li Ding,Michelle L. Paulson,Michelle L. Paulson,Beatriz E. Marciano,Juan Gea-Banacloche,Jordan S. Orange,Jennifer Cuellar-Rodriguez,Dennis D. Hickstein,Steven M. Holland +25 more
TL;DR: GATA2 joins RUNX1 and CEBPA not only as a familial leukemia gene but also as a cause of a complex congenital immunodeficiency that evolves over decades and combines predisposition to infection and myeloid malignancy.
Journal ArticleDOI
Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency
Rachel E. Dickinson,Helen Griffin,Venetia Bigley,Louise N. Reynard,Rafiqul Hussain,Muzlifah Haniffa,Jeremy H. Lakey,Thahira Rahman,Xiao-Nong Wang,Naomi McGovern,Sarah Pagan,Sharon Cookson,David McDonald,Ignatius Chua,Jonathan Wallis,Andrew J. Cant,Michael Wright,Michael Wright,Bernard Keavney,Patrick F. Chinnery,John Loughlin,Sophie Hambleton,Mauro Santibanez-Koref,Matthew Collin +23 more
TL;DR: Because GATA2 is the only common mutated gene in 4 unrelated persons, it is highly probable to be the cause of dendritic cell, monocyte, B, and natural killer lymphoid deficiency and constitutes a new genetic form of heritable immunodeficiency and leukemic transformation.
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