Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome.
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 myeloproliferative disorder (TMD), a preleukemic 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 hematopoiesis. 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 trisomy of approximately 80% of Hsa21 perturb megakaryopoiesis but are insufficient to induce leukemia.
Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London, UK.
Kate A
KA
Alford
Amy
A
Slender
Lesley
L
Vanes
Zhe
Z
Li
Elizabeth M C
EM
Fisher
Dean
D
Nizetic
Stuart H
SH
Orkin
Irene
I
Roberts
Victor L J
VL
Tybulewicz
D000748:Anemia, Macrocytic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D038042:Myelopoiesis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse