Triplications of human chromosome 21 orthologous regions in mice result in expansion of megakaryocyte-erythroid progenitors and reduction of granulocyte-macrophage progenitors
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Chunhong Liu1,*, Tao Yu1,2,*, Zhuo Xing1,*, Xiaoling Jiang1,*, Yichen Li1, Annie Pao1, Justin Mu1, Paul K. Wallace3, George Stoica4, Andrei V. Bakin5 and Y. Eugene Yu1,6
1The Children's Guild Foundation Down Syndrome Research Program, Genetics and Genomics Program and Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
2Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
3Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
4Department of Pathobiology, Texas A&M University, College Station, TX 77843, USA
5Genetics and Genomics Program and Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
6Genetics, Genomics and Bioinformatics Program, State University of New York at Buffalo, Buffalo, NY 14263, USA
Y. Eugene Yu, email: [email protected]
Keywords: Down syndrome; myeloproliferative disorder; genetically engineered mouse models; megakaryocyte-erythrocyte progenitors; granulocyte-monocyte progenitors
Received: August 21, 2017 Accepted: November 20, 2017 Published: December 19, 2017
Individuals with Down syndrome (DS) frequently have hematopoietic abnormalities, including transient myeloproliferative disorder and acute megakaryoblastic leukemia which are often accompanied by acquired GATA1 mutations that produce a truncated protein, GATA1s. The mouse has been used for modeling DS based on the syntenic conservation between human chromosome 21 (Hsa21) and three regions in the mouse genome located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. To assess the impact of the dosage increase of Hsa21 gene orthologs on the hematopoietic system, we characterized the related phenotype in the Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+ model which carries duplications spanning the entire Hsa21 orthologous regions on Mmu10, Mmu16 and Mmu17, and the Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+;Gata1Yeym2 model which carries a Gata1s mutation we engineered. Both models exhibited anemia, macrocytosis, and myeloproliferative disorder. Similar to human DS, the megakaryocyte-erythrocyte progenitors (MEPs) and granulocyte-monocyte progenitors (GMPs) were significantly increased and reduced, respectively, in both models. The subsequent identification of all the aforementioned phenotypes in the Dp(16)1Yey/+ model suggests that the causative dosage sensitive gene(s) are in the Hsa21 orthologous region on Mmu16. Therefore, we reveal here for the first time that the human trisomy 21-associated major segmental chromosomal alterations in mice can lead to expanded MEP and reduced GMP populations, mimicking the dynamics of these myeloid progenitors in DS. These models will provide the critical systems for unraveling the molecular and cellular mechanism of DS-associated myeloproliferative disorder, and particularly for determining how human trisomy 21 leads to expansion of MEPs as well as how such an alteration leads to myeloproliferative disorder.
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