A Myeloproliferative Disorder in the Tc1 Mouse Model of Down Syndrome

Abstract

Down syndrome (DS) children have a one in ten chance of being diagnosed with leukemia within the first ten years of life. Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) that accounts for nearly 50% of these leukemias. AMKL is associated with a self-regressing neoplasia found almost exclusively in DS newborns called Transient Myeloproliferative Disorder (TMD). In all cases of TMD and DS-AMKL, leukemic blast cells show mutations in the gene encoding the hematopoietic transcription factor GATA1, resulting in production of a truncated form of the protein called GATA1s. Mutations in GATA1 are not seen in non-DS-AMKL or other DS leukemias and it is clear both trisomy of human chromosome 21 (HSA21) and a mutation in GATA1 are required for the development of both TMD and AMKL. However, it is unknown which genes on HSA21 need to be trisomic in order to predispose an individual with DS to AMKL. Our group has generated mice (termed the Tc1 mice) that contain an almost complete, freely segregating copy of HSA21. These mice display phenotypic features of DS. We have examined adult hematopoiesis in these mice. Blood samples taken from a cohort of Tc1 mice were examined from 4 weeks until 60 weeks of age. Complete blood cell counts show that whilst the mice do not develop leukemia they displayed persistent macrocytosis and had reduced erythrocyte numbers. Crossing the Tc1 mice with mice that express GATA1s protein did not perturb or exacerbate this phenotype. Over the age of 15 months more than 50% of Tc1 mice examined were found to have developed splenomegaly. These mice displayed megakaryocyte hyperplasia and had increased numbers of cells of the erythroid lineage. In vitro colony forming assays demonstrated an increase in the frequency of megakaryocytic and granulocyte-macrophage progenitors in the spleen, consistent with extramedullary hematopoiesis. In the bone marrow, no abnormalities were seen in the lineage-, c-Kit+, Sca1+ (LSK) compartment, however there was a significant increase in the percentage of common myeloid progenitors (CMP) and a corresponding decrease in megakaryocyte-erythrocyte progenitors (MEP). This suggests a possible block in development from CMP to MEP. These data demonstrate defects in hematopoietic development in a proportion of adult Tc1 mice. However, preliminary data suggest that these mice do not develop a neonatal myeloproliferative disorder that is comparable with human TMD. It may be that the phenotype seen in the adult Tc1 mice is due to defects in hematopoietic progenitors that are different to those responsible for development of TMD and DS-AMKL. This mouse model may therefore provide a useful tool to examine the role of HSA21 genes in adult hematopoietic disorders.