Modeling Myelodysplastic Syndromes with human iPSCs
Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by ineffective hematopoiesis and a propensity for progression to acute myeloid leukemia (AML). Once thought to be rare disorders, MDS are now recognized to be among the most common blood cancers, but their pathogenesis remains poorly understood. Current tools to study MDS are limited: animal models do not faithfully recapitulate human MDS, no cell lines exist and primary cells are heterogeneous and hard to grow ex vivo.
We have recently established the first iPSC models of MDS that offer exciting new possibilities for the study of the cellular and molecular pathogenesis of MDS and its genetics and clonal evolution. They also provide a powerful platform for phenotype-based genetic and chemical screens to identify new therapeutic targets.
Modeling disease-associated chromosomal deletions with CRISPR
Chromosomal deletions associated with human disease are common in normal and cancer genomes and may constitute an important component of the “missing heritability” of complex diseases and the “dark matter” of cancer genetics. Unlike translocations or point mutations, chromosomal deletions are difficult to study because physical mapping in primary patient material is limited by the rarity of informative cases and incomplete conservation of synteny complicates their modeling in mice.
We developed an approach to model disease-related chromosomal deletions in human iPSCs. By using modified Cre-loxP and CRISPR/Cas9 technologies we can engineer hemizygous deletions of specific chromosomal fragments. These allow us to functionally map disease phenotypes and identify candidate disease genes through phenotype-rescue screens.