Modeling Genetic Modifiers of Down Syndrome Leukemogenesis

Background
Children with Down syndrome (Trisomy 21) exhibit numerous blood abnormalities and a predisposition to leukemia.  Neonates with Down syndrome are often born with a pre-leukemia termed transient myeloproliferative disorder (TMD). Many subsequently develop acute megakaryoblastic leukemia (AMKL) by age 4 which is associated with significant treatment-related toxicity. Both TMD and AMKL are accompanied by mutations in a gene named GATA1 that is required for normal blood development.

Project Goal
My research proposal focuses on how an extra chromosome 21 and the mutant GATA1 affects blood development. We are using induced pluripotent stem cells, a renewable human cell source that we generated from blood cells of patients with Down syndrome and TMD, to define step-by-step the pathways of aberrant blood formation and progression to leukemia associated with trisomy 21.