Understanding how genes interact to coordinate tissue development and cause human disease is a fundamental problem in biomedicine. We are drawn to this puzzle through studies of Down syndrome (DS, trisomy 21, T21) and the hematopoietic transcription factor GATA-1. DS causes multiple hematopoietic abnormalities including polycythemia, thrombocytopenia and two related clonal disorders: transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia (AMKL). The latter disorders are part of a multi-step progression that requires somatic GATA1 mutations resulting in an 83 amino acid truncated protein termed GATA-1s. Similar germline mutations in GATA1 cause anemia in euploid patients. These clinical observations raise several interesting questions: 1) what genes on chromosome 21 (HSA21) regulate hematopoiesis? 2) How does the GATA-1 amino terminus facilitate hematopoietic differentiation? 3) How do the same GATA1 mutations cause different diseases in patients with and without T21? and 4) How do T21 and GATA1 mutations synergize uniquely to cause myeloproliferation? Murine models have provided important information, but do not fully recapitulate the human diseases. We are studying these problems using human fetal liver specimens and induced pluripotent stem cells (iPSCs) generated from patients with DS, TMD, and GATA1s-associated anemias. Preliminary studies indicate that iPSCs with T21 and GATA-1s exhibit distinct hematopoietic abnormalities that recapitulate many aspects of the associated human disorders. Now, we will perform systematic characterization of primitive (yolk sac-type) and definitive (fetal liver-type) hematopoiesis in iPSCs with T21, GATA-1s or both. We will manipulate the expression of candidate HSA21 genes in iPSCs to identify those responsible for DS-associated blood abnormalities. In parallel, we will use our patient-derived iPSCs and a MEP-like cell line to study how GATA1s mutations dysregulate hematopoietic gene expression and investigate the associated mechanisms through efforts to identify proteins that interact with the GATA-1 amino terminus. Our studies will elucidate how GATA1 and HSA21 genes, separately and together, modulate hematopoiesis. More generally, we hope to create new paradigms in which other hematopoietic diseases can be modeled through creation and manipulation of patient-derived iPSCs.

Public Health Relevance

Infants and children with Down syndrome suffer from a unique constellation of blood diseases, including altered blood counts, myeloproliferative disease and leukemia. To study these diseases, we are creating and analyzing induced pluripotent stem cells from Down syndrome patients. Our work will provide new insights into blood cell production, generate new experimental tools for the biomedical community and elucidate new strategies to study other inherited blood diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Hematology (MCH)
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Bishop, Terry Rogers
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Children's Hospital of Philadelphia
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Tasian, Sarah K; Casas, Jessica A; Posocco, David et al. (2018) Mutation-specific signaling profiles and kinase inhibitor sensitivities of juvenile myelomonocytic leukemia revealed by induced pluripotent stem cells. Leukemia :
Giani, Felix C; Fiorini, Claudia; Wakabayashi, Aoi et al. (2016) Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells. Cell Stem Cell 18:73-78
Byrska-Bishop, Marta; VanDorn, Daniel; Campbell, Amy E et al. (2015) Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus. J Clin Invest 125:993-1005