Cellular alchemy meets genome engineering
We use human pluripotent stem cells to understand the mechanisms of malignant and non-malignant blood diseases and to develop new therapies. We are harnessing somatic cell reprogramming and genetic engineering technologies to develop new models of normal and abnormal hematopoiesis. By capturing and introducing disease-associated genetic mutations and large chromosomal deletions in patient-derived induced pluripotent stem cells (iPSCs) we study their phenotypic and functional consequences, attempt to reconstruct the genetic history of leukemia progression and seek to identify new therapeutic targets through genetic screens.
Genotype-driven modeling of Myelodysplastic Syndromes
Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by ineffective hematopoiesis - manifested as peripheral blood cytopenia and dysplastic bone marrow (BM) - and a propensity for progression to BM failure or acute myeloid leukemia (AML) with poor prognosis. Although relatively common diseases, their pathogenesis is poorly understood.
We have recently established iPSC models of MDS that offer exciting new possibilities for the study of the molecular pathogenesis of MDS and the investigation of its genetics, clonal evolution and progression to leukemia and can provide a powerful platform for phenotype-based genetic and chemical screens to identify new therapeutic targets. We have also developed new strategies, combining AAV-mediated gene targeting with modified Cre-lox technology, as well as with the Cas9-CRISPR system, to engineer targeted chromosomal deletions in human iPSCs. These offer new opportunities to interrogate the functional consequences of large copy number variants associated with human cancer.
