title: Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome.
abstract: 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.
authors: Ben May Department for Cancer Research, University of Chicago, IL 60611, USA.
authors: Gina
authors: G
authors: Kirsammer
authors: Sarah
authors: S
authors: Jilani
authors: Hui
authors: H
authors: Liu
authors: Elizabeth
authors: E
authors: Davis
authors: Sandeep
authors: S
authors: Gurbuxani
authors: Michelle M
authors: MM
authors: Le Beau
authors: John D
authors: JD
authors: Crispino
mesh_terms: D000818:Animals; D002648:Child; D002675:Child, Preschool; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D023461:Myeloid Progenitor Cells / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000150:complications / Q000235:genetics* / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics; D040641:Quantitative Trait Loci; D014314:Trisomy / Q000235:genetics* / Q000473:pathology
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D015513:Oncogene Proteins; C493726:Runx1 protein, mouse