Myeloproliferative Disease in a Mouse Model of Down Syndrome.

Abstract

Trisomy 21 causes human Down syndrome (DS), a heterogeneous group of phenotypes including marked predisposition to leukemia. Children with Down syndrome are 500 times more likely to develop acute megakaryoblastic leukemia (AMKL) than other children. Furthermore, non-DS children with AMKL often have acquired trisomy 21 in their leukemic clones, suggesting that trisomy 21 in hematopoietic cells contributes to leukemic transformation. To better understand the impact of trisomy 21 on blood cell homeostasis and leukemia, we studied hematopoiesis in the Ts65Dn mouse model of Down syndrome. Ts65Dn mice harbor a segmental trisomy for mouse chromosome 16, homologous to human chromosome 21, and display many of the phenotypes associated with human DS, including craniofacial anomalies and learning deficits. To define the hematopoietic parameters for this strain, we performed monthly complete blood counts for a cohort of trisomic mice and their disomic littermates and discovered the development of progressive thrombocytosis and mild anemia in trisomic animals. Increased numbers of CD41+ megakaryocytes with lower modal ploidy were detected in the bone marrow and spleen of Ts65Dn mice as early as three months of age. Over time, expansion of the megakaryocyte population was accompanied by a decrease in TER119+ cells in the bone marrow, myelofibrosis, splenomegaly, and extramedullary hematopoiesis. Colony forming assays demonstrated increased colony forming ability in the spleens of trisomic mice along with variable decreased hematopoiesis in the bone marrow. Further, characterization of stem cells in the bone marrow indicated a hyperproliferative stem cell population. Importantly, the mice did not develop malignant leukemia by the age of 18 months and no mutations were found in the blood transcription factor GATA1, which is commonly affected in human AMKL. While Ts65Dn mice do not develop the AMKL seen in humans with DS, our results indicate that, trisomy 16 can cause hyperproliferation of the myeloid lineages, extramedullary hematopoiesis, and bone marrow fibrosis in mice. Additionally, these results suggest that trisomy 21 in humans may initiate a similar process in hematopoietic stem cells, which may contribute to leukemogenesis. Unexpectedly, this phenotype also bears significant resemblance to the human myeloproliferative disease chronic idiopathic myelofibrosis (CIMF). These findings may provide insight into the origins and progression of human myeloid diseases, including AMKL and CIMF.