Submitted April 16, 2007
Accepted September 12, 2007
Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome
Gina Kirsammer, Sarah Jilani, Hui Liu, Elizabeth Davis, Sandeep Gurbuxani, Michelle M. Le Beau, and John D. Crispino*
Division of Hematology/Oncology; Department of Medicine, Northwestern University, Chicago, IL, United States
Ben May Department of Cancer Research, University of Chicago, Chicago, IL, United States
Section of Hematology/Oncology; Department of Medicine, University of Chicago, Chicago, IL, United States
Department of Pathology, University of Chicago, Chicago, IL, United States
* Corresponding author; email: j-crispino{at}northwestern.edu.
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 to 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.
