Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome

Abstract

Trisomy of human chromosome 21 (Hsa21) results in Down syndrome (DS), a disorder that affects many aspects of physiology, including hematopoiesis. DS children have greatly increased rates of acute lymphoblastic leukemia and acute megakaryoblastic leukemia (AMKL); DS newborns present with transient myelo-proliferative disorder (TMD), a preleuke-mic form of AMKL. TMD and DS-AMKL almost always carry an acquired mutation in GATA1 resulting in exclusive synthesis of a truncated protein (GATA1s), suggesting that both trisomy 21 and GATA1 mutations are required for leukemogenesis. To gain further understanding of how Hsa21 contributes to hematopoietic abnormalities , we examined the Tc1 mouse model of DS, which carries an almost complete freely segregating copy of Hsa21, and is the most complete model of DS available. We show that although Tc1 mice do not develop leukemia, they have macrocytic anemia and increased extramedullary he-matopoiesis. Introduction of GATA1s into Tc1 mice resulted in a synergistic increase in megakaryopoiesis, but did not result in leukemia or a TMD-like phenotype , demonstrating that GATA1s and tri-somy of approximately 80% of Hsa21 perturb megakaryopoiesis but are insufficient to induce leukemia. (Blood. 2010; 115(14):2928-2937) Introduction Down syndrome (DS) results from trisomy of human chromosome 21 (Hsa21, trisomy 21) and is the most common chromosomal disorder in liveborn humans. 1 Persons with DS have an increased risk of developing several hematologic defects, including macrocy-tosis, neutrophilia, thrombocytopenia, and polycythemia. 2-5 In addition, they also have an increased incidence of both acute lymphoblastic leukemia (ALL) and acute megakaryoblastic leuke-mia (AMKL) in childhood. 6 Approximately 10% of DS newborns are born with a transient myeloproliferative disorder (TMD), and, of these, 20% to 30% progress to AMKL by 4 years of age. 7,8 Both diseases are characterized by the presence of a clonal population of megakaryoblasts in the blood. However, whereas TMD is a spontaneously regressing neoplasia, AMKL is life threatening and requires chemotherapy. An important step in understanding the origins of these diseases was the discovery that almost all cases of TMD and AMKL have acquired and clonal mutations in exon 2 of the X-linked GATA1 gene, which codes for the GATA1 transcription factor. 9-14 The effect of these mutations is to prevent expression of full-length GATA1 from the normal ATG initiation codon, forcing translation to initiate at an ATG codon in exon 3, thus resulting in the synthesis of a truncated GATA1 protein termed GATA1 short (GATA1s). Examination of GATA1 mutations shows that in any one person, the mutation found in AMKL cells is the same as the mutation seen first in TMD, thus leading to the proposal that TMD is a preleukemic disease that can eventually develop into AMKL, presumably as a result of further mutations. 10,15 Interestingly, although GATA1 mutations are found in all cases of DS-AMKL, no such mutations are seen in non-DS-AMKL. 13,14 Taken together...

Evolution of myeloid leukemia in children with Down syndrome

“…These transgenic mouse models provided important insight into the function of a number of genes on chromosome 21 [18][19][20]. Tc1 mice have macrocytic anemia and increased extramedullary hematopoiesis [18]. Ts65Dn mice, which are trisomic for 104 orthologs of Hsa21 genes, display persistent macrocytosis and develop a myeloproliferative disease characterized by megakaryocyte hyperplasia and dysplasia, and myelofibrosis [19].…”

“…Some used a series of transgenic mouse models, including the Tc1 mouse, which contains a copy of most of Hsa21 [18], and other mice containing additional copies of all or part of mouse chromosomal regions corresponding to Hsa21 [19,20]. These transgenic mouse models provided important insight into the function of a number of genes on chromosome 21 [18][19][20]. Tc1 mice have macrocytic anemia and increased extramedullary hematopoiesis [18].…”

“…Some researchers investigated gene expression by human embryonic stem (ES) cells or induced pluripotent stem (iPS) cells derived from primary trisomy 21 samples, showing an intrinsic disturbance of multi-lineage myeloid hematopoiesis at specific stages [16,17]. Some used a series of transgenic mouse models, including the Tc1 mouse, which contains a copy of most of Hsa21 [18], and other mice containing additional copies of all or part of mouse chromosomal regions corresponding to Hsa21 [19,20]. These transgenic mouse models provided important insight into the function of a number of genes on chromosome 21 [18][19][20].…”

Leukemogenesis in Down syndrome

“…The Tc1 mice show macrocytic anemia and an increased number of megakaryocytes with extramedullary hematopoiesis in the elderly. On the contrary, significant changes in frequencies of megakaryocytes, erythroid, and myeloid progenitors were not observed in the fetal liver [39]. Ts16 mice were generated by crossing mice with Robertsonian translocation Rb (14;16) and Rb (9;16), resulting in animals trisomic for mouse chromosome 16 (synthetic of human chromosome 21).…”

Trisomy 21 leukemias: finding the hits that matter

“…Complementary to the in vitro work of De Vita et al, the Tybulewicz laboratory has also investigated in vivo hematopoiesis in the Tc1 mouse model of DS, created via germ line transmission of transchromosomic mESCs containing B70% of Hsa21 (Alford et al, 2010). These mice display altered hematopoiesis, with extramedullary hematopoiesis.…”