|
|
Blood, 15 January 2008, Vol. 111, No. 2, pp. 767-775.
Prepublished online as a Blood First Edition Paper on September 27, 2007; DOI 10.1182/blood-2007-04-085670.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome
Gina Kirsammer1,2,
Sarah Jilani1,
Hui Liu1,
Elizabeth Davis3,
Sandeep Gurbuxani4,
Michelle M. Le Beau3, and
John D. Crispino1,2
1 Ben May Department for Cancer Research, University of Chicago, IL;
2 Division of Hematology/Oncology, Northwestern University, Chicago, IL;
3 Section of Hematology/Oncology, and
4 Department of Pathology, University of Chicago, IL
Children with Down syndrome (DS) display macrocytosis, thrombocytosis, and a 500-fold increased risk of developing megakaryocytic leukemia; however, the specific effects of trisomy 21 on hematopoiesis remain poorly defined. To study this question, we analyzed blood cell development in the Ts65Dn mouse model of DS. Ts65Dn mice are trisomic for 104 orthologs of Hsa21 genes and are the most widely used mouse model for DS. We discovered that Ts65Dn mice display persistent macrocytosis and develop a myeloproliferative disease (MPD) characterized by profound thrombocytosis, megakaryocyte hyperplasia, dysplastic megakaryocyte morphology, and myelofibrosis. In addition, these animals bear distorted hematopoietic stem and myeloid progenitor cell compartments compared with euploid control littermates. Of the 104 trisomic genes in Ts65Dn mice, Aml1/Runx1 attracts considerable attention as a candidate oncogene in DS–acute megakaryoblastic leukemia (DS-AMKL). To determine whether trisomy for Aml1/Runx1 is essential for MPD, we restored disomy at the Aml1/Runx1 locus in the Ts65Dn strain. Surprisingly, trisomy for Aml1/Runx1 is not required for megakaryocyte hyperplasia and myelofibrosis, suggesting that trisomy for one or more of the remaining genes can promote this disease. Our studies demonstrate the potential of DS mouse models to improve our understanding of chromosome 21 gene dosage effects in human hematologic malignancies.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
Of mice and Down syndrome
- Jeffrey W. Taub
Blood 2008 111: 472.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
S. Salek-Ardakani, G. Smooha, J. de Boer, N. J. Sebire, M. Morrow, L. Rainis, S. Lee, O. Williams, S. Izraeli, and H. J.M. Brady
ERG Is a Megakaryocytic Oncogene
Cancer Res.,
June 1, 2009;
69(11):
4665 - 4673.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. K. Wiseman, K. A. Alford, V. L.J. Tybulewicz, and E. M.C. Fisher
Down syndrome--recent progress and future prospects
Hum. Mol. Genet.,
April 15, 2009;
18(R1):
R75 - R83.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Stankiewicz and J. D. Crispino
ETS2 and ERG promote megakaryopoiesis and synergize with alterations in GATA-1 to immortalize hematopoietic progenitor cells
Blood,
April 2, 2009;
113(14):
3337 - 3347.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Malinge, S. Izraeli, and J. D. Crispino
Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome
Blood,
March 19, 2009;
113(12):
2619 - 2628.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. L. Carmichael, I. J. Majewski, W. S. Alexander, D. Metcalf, D. J. Hilton, C. A. Hewitt, and H. S. Scott
Hematopoietic defects in the Ts1Cje mouse model of Down syndrome
Blood,
February 26, 2009;
113(9):
1929 - 1937.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
