Hematopoiesis in the Ts65Dn Mouse Model of Down Syndrome (DS) Recapitulates Many Features of Human DS.

Down syndrome-associated acute megakaryocytic leukemia (DS-AMKL) is a complex malignancy that evolves in hematopoietic progenitors with trisomy 21 that acquire a somatic mutation in the blood transcription factor GATA1. The mechanistic relationship between these two genetic factors that leads to leukemia is poorly understood. In order to study the interplay between trisomy 21 and GATA1 mutations, we are developing a mouse model of this malignancy. The Ts65Dn mouse, which contains a segmental trisomy for mouse chromosome 16, homologous to human 21, has been reported to display several of the cognitive and craniofacial phenotypes seen in humans with DS, but the hematopoietic system has not been assessed as a model for blood development in humans with DS. We have evaluated adult hematopoiesis in the Ts65Dn strain by comparing monthly complete blood counts (CBC) of peripheral blood from 14 trisomic and 20 disomic littermates. Similar to humans with DS, Ts65Dn trisomic mice display persistent erythrocyte macrocytosis, with values at the high end of the normal range. Trisomic mice also harbor decreased numbers of red blood cells, mildly elevated platelet counts, a higher percentage of monocytes and a lower hemoglobin concentration. Interestingly infants with DS frequently display thrombocytosis. In addition, we have characterized fetal liver hematopoiesis in the Ts65Dn strain by FACS analysis of hematopoietic precursors and by performing colony assays. In general, we did not detect any significant differences in erythroid, myeloid, or megakaryocytic colony formation between trisomic or disomic fetuses. Likewise flow cytometry for CD34, TER119, and CD41 demonstrated overall similar numbers of cells in these compartments for Ts65Dn mice and disomic littermates. However, one of seven trisomic embryos displayed a significant increase in the proportion of CD34+ cells with concomitant decrease in both Ter119+ and CD41+ populations. In addition, cells from this fetal liver gave rise to seven-fold and three-fold increases in BFU-E and CFU-Mk colonies respectively, with no change in the CFU-GM. Although the sample size is small, these findings suggest that a subset of Ts65Dn trisomic fetuses exhibit aberrant hematopoiesis. Taken together, our study indicates that the Ts65Dn trisomic mouse may be an excellent model to study human DS hematopoiesis.