Intrinsic and Extrinsic Factors Contributing to Trisomy 21 Preleukemia

Children with Down syndrome have a significantly increased risk of developing preleukemia during early childhood compared to children without Down syndrome. Our proposal aims to determine the molecular mechanisms that underlie the predisposition of trisomy 21 versus disomic hematopoietic stem cells towards initiating the preleukemic condition transient abnormal myelopoiesis. We are employing a combination of multi- omic analyses of human primary trisomy 21 fetal liver samples and subsequent functional interrogation using CRISPR/Cas9-mediated genome editing to uncover fundamental mechanisms and therapeutic targets of preleukemia in Down syndrome.