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Prepublished online as a Blood First Edition Paper on March 20, 2003; DOI 10.1182/blood-2002-11-3599.
Submitted December 2, 2002
Accepted March 11, 2003
Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21
Liat Rainis, Dan Bercovich, Sabine Strehl, Andrea Teigler-Schlegel, Batia Stark, Jan Trka, Ninette Amariglio, Andrea Biondi, Inna Muler, Gideon Rechavi, Helena Kempski, Oskar A Haas, and Shai Izraeli*
Department of Pediatric Hemato-Oncology, Safra Childrens Hospital, Sheba Medical Center, Affiliated to Tel-Aviv University, Tel-Hashomer, Israel
Genetic Institute, Tel-Aviv Souraski Medical Center, Affiliated toTel-Aviv University, Tel-Aviv, Israel
Department of Human Molecular Genetics, Migal - Glailee Technological Center, Kyriat Shemona, Israel
Department of Molecular and Cytogenetics, Children's Cancer Research Institute, St Anna Children's Hospital, Vienna, Austria
Oncogenetic Laboratory, Children's University Hospital, Giessen, Germany
Department of Pediatric Hemato-Oncology, Schneider's Childrens' Medical Center, Petach-Tiqva, Israel
Laboratory of Molecular Genetics, CLIP, 2nd Department of Pediatrics, 2nd Medical School, Charles University, Prague, Czech Republic
Centro M Tettamanti, Clinica Pediatrica, Universita Milano-Bicocca, Monza, Italy
Institute of Child Health, Great Ormond Street Hospital, London, United Kingdom
* Corresponding author; email: sizraeli{at}post.tau.ac.il.
Patients with Down syndrome (DS) frequently develop two kinds of clonal megakaryocytosis: a common, congenital, spontaneously resolving, transient myeloproliferative disorder (TMD) and less common childhood acute megakaryoblastic leukemia (AMKL). Recently, acquired mutations in exon 2 of GATA1, an X-linked gene encoding a transcription factor that promotes megakaryocytic differentiation, were described in six DS patients with AMKL. The mutations prevent the synthesis of the full length GATA1 but allow the synthesis of a shorter GATA1 protein (GATA1s) that lacks the transactivation domain. To test if mutated GATA1 is involved in the initiation of clonal megakaryoblastic proliferation or in the progression to AMKL, we screened 35 DS patients with either AMKL or TMD and 7 non-DS children with AMKL for mutations in exon 2 of GATA1. Mutations were identified in 16/18 DS patients with AMKL, in 16/17 DS patients with TMD and in two identical twins with AMKL and acquired trisomy 21. Analysis revealed various types of mutations in GATA1 including deletion/insertions, splice mutations, nonsense and missense point mutations - all of which prevent the generation of full length GATA1, but preserve the translation of GATA1s. We also show that the likely mechanism of generation of GATA1 isoforms is alternative splicing of exon 2 rather than, or in addition to, alternative translation initiation as was proposed before. These findings suggest that acquired intrauterine inactivating mutations in GATA1 and generation of GATA1s cooperate frequently with trisomy 21 in initiating megakaryoblastic proliferation but are insufficient for progression to AMKL.
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|
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|
|
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|
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|
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|
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|
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|
|
|
|
|
|
|
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110(6):
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
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103(38):
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|
|
|
|
|
|
|
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February 15, 2006;
107(4):
1570 - 1581.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. L. Stachura, S. T. Chou, and M. J. Weiss
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January 1, 2006;
107(1):
87 - 97.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Kuhl, A. Atzberger, F. Iborra, B. Nieswandt, C. Porcher, and P. Vyas
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October 1, 2005;
25(19):
8592 - 8606.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Rainis, T. Toki, J. E. Pimanda, E. Rosenthal, K. Machol, S. Strehl, B. Gottgens, E. Ito, and S. Izraeli
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September 1, 2005;
65(17):
7596 - 7602.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Vannucchi, A. Pancrazzi, P. Guglielmelli, S. Di Lollo, C. Bogani, G. Baroni, L. Bianchi, A. R. Migliaccio, A. Bosi, and F. Paoletti
Abnormalities of GATA-1 in Megakaryocytes from Patients with Idiopathic Myelofibrosis
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September 1, 2005;
167(3):
849 - 858.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Groet, C. Mulligan, M. Spinelli, A. Serra, S. McElwaine, F. E. Cotter, F. Dagna-Bricarelli, G. Saglio, G. Basso, and D. Nizetic
Independent clones at separable stages of differentiation, bearing different GATA1 mutations, in the same TMD patient with Down syndrome
Blood,
September 1, 2005;
106(5):
1887 - 1888.
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Pan, O. Ohneda, K. Ohneda, F. Lindeboom, F. Iwata, R. Shimizu, M. Nagano, N. Suwabe, S. Philipsen, K.-C. Lim, et al.
Graded Levels of GATA-1 Expression Modulate Survival, Proliferation, and Differentiation of Erythroid Progenitors
J. Biol. Chem.,
June 10, 2005;
280(23):
22385 - 22394.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. C. Hughan, Y. Senis, D. Best, A. Thomas, J. Frampton, P. Vyas, and S. P. Watson
Selective impairment of platelet activation to collagen in the absence of GATA1
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June 1, 2005;
105(11):
4369 - 4376.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Toki, F. Katsuoka, R. Kanezaki, G. Xu, H. Kurotaki, J. Sun, T. Kamio, S. Watanabe, S. Tandai, K. Terui, et al.
Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment
Blood,
April 15, 2005;
105(8):
3100 - 3108.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Ge, M. L. Stout, D. A. Tatman, T. L. Jensen, S. Buck, R. L. Thomas, Y. Ravindranath, L. H. Matherly, and J. W. Taub
GATA1, Cytidine Deaminase, and the High Cure Rate of Down Syndrome Children With Acute Megakaryocytic Leukemia
J Natl Cancer Inst,
February 2, 2005;
97(3):
226 - 231.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Rainis, E. Rosenthal, S. Strehl, O. A. Haas, and S. Izraeli
The ERG Gene in Normal and Malignant Megakaryopoiesis.
Blood (ASH Annual Meeting Abstracts),
November 16, 2004;
104(11):
3431 - 3431.
[Abstract]
|
|
|
|
|
|
|
H. Harigae, G. Xu, T. Sugawara, I. Ishikawa, T. Toki, and E. Ito
The GATA1 mutation in an adult patient with acute megakaryoblastic leukemia not accompanying Down syndrome
Blood,
April 15, 2004;
103(8):
3242 - 3243.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Ahmed, A. Sternberg, G. Hall, A. Thomas, O. Smith, A. O'Marcaigh, R. Wynn, R. Stevens, M. Addison, D. King, et al.
Natural history of GATA1 mutations in Down syndrome
Blood,
April 1, 2004;
103(7):
2480 - 2489.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R P S Bajwa, R Skinner, K P Windebank, and M M Reid
Demographic study of leukaemia presenting within the first 3 months of life in the Northern Health Region of England
J. Clin. Pathol.,
February 1, 2004;
57(2):
186 - 188.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Ge, T. L. Jensen, M. L. Stout, R. M. Flatley, P. J. Grohar, Y. Ravindranath, L. H. Matherly, and J. W. Taub
The Role of Cytidine Deaminase and GATA1 Mutations in the Increased Cytosine Arabinoside Sensitivity of Down Syndrome Myeloblasts and Leukemia Cell Lines
Cancer Res.,
January 15, 2004;
64(2):
728 - 735.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Gurbuxani, P. Vyas, and J. D. Crispino
Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome
Blood,
January 15, 2004;
103(2):
399 - 406.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Shimada, G. Xu, T. Toki, H. Kimura, Y. Hayashi, and E. Ito
Fetal origin of the GATA1 mutation in identical twins with transient myeloproliferative disorder and acute megakaryoblastic leukemia accompanying Down syndrome
Blood,
January 1, 2004;
103(1):
366 - 366.
[Full Text]
[PDF]
|
|
|
|
|
