Genetic Dissection of Trisomy 21-TMD Using Human Pluripotent Stem Cells

Background
Individuals with Down Syndrome (Trisomy 21, T21), are at a much greater risk of developing Acute Megakaryoblastic Leukemia (AMKL) than the general population. AMKL in T21 usually affects children under the age of 10, with a mortality of 10-25%. Development of T21-AMKL is preceded by another condition called Transient Myeloproliferative Disorder (TMD). Roughly 20% of T21-TMD cases develop into T21-AMKL, and both T21-TMD and T21-AMKL are associated with mutations in the GATA1 protein. Mouse models for T21 do not develop either TMD or AMKL, hence alternative strategies are required to study the molecular causes of T21-TMD/AMKL. With this in mind, I am using a system to study human blood development in vitro.

Human induced pluripotent stem cells (iPS) are somatic human cells that have been genetically reprogrammed, so that they become pluripotent, i.e.,  they have the potential to develop into any specific tissue when treated with appropriate cytokines and growth factors. These cells can be used to study mechanisms of disease development in cases where animal models do not accurately recapitulate human disease.

Project Goal
This proposal describes the use of iPS cells to uncover the genetic events underlying development of T21-TMD. I will use T21 iPS cells containing the GATA1 mutation to identify genes that are affected by the mutation. In addition to identifying genetic pathways that lead to leukemogenesis, this proposal will also confirm the viability of using iPS cell technology to study human disease.