We aim to createa disease-in-a-dish model to understand myeloid leukemia in children with Down syndrome (ML-DS). Trisomy 21 (T21), or Down syndrome (DS), is a genetic condition caused by an extra copy of chromosome 21. This leads to developmental differences, including distinct blood cell abnormalities. Young children with DS have a higher risk of developing blood cancers, which begins with a pre-leukemic condition, transient abnormal myelopoiesis (TAM), before birth, after acquiring a genetic change in the GATA1 gene. Later it can develop into leukemia if more mutations arise. To date, there is no efficient way to predict or prevent the disease progression.

The beginning of the DS blood cancer is understudied due to the difficulties of studying the events that occur before birth. Studies have shown a specific progenitor cell in the developing liver as the likely cell of origin for TAM. In developing DS tissues, this cell is more abundant and persists longer, even without GATA1 mutations. Therefore, we propose to combine DS induced pluripotent stem cells with the latest blood stem cell generation protocol to establish a disease in a dish model. By comparing our existing dataset collected from developmental tissues and patient samples (TAM and ML-DS), we will be able to validate our disease model. We will provide the scientists with a tool to study blood abnormalities in Down syndrome, and shed insights into childhood leukemia development and new therapies.