NIH Research Festival
Familial platelet disorder with associated myeloid malignancy (FPDMM) is a rare, autosomal dominant disease caused by heterozygous germline mutations in RUNX1. Patients have a bleeding disorder characterized by dysmegakaryopoiesis, thrombocytopenia, and platelet dysfunction. Importantly, more than a third of patients develop myelodysplastic syndrome or acute myeloid leukemia (MDS/AML). Because of the variable penetrance of malignancies in FPDMM, we sought to identify secondary germline mutations that contribute to leukemogenesis. FPDMM patients from a family carrying a heterozygous nonsense mutation (Y260X) in RUNX1 were subjected to whole exome sequencing (WES), including two patients who developed hematological malignancies. Using a candidate gene approach, we identified three germline variants found only in the patients who developed malignancies. Moreover, we sought to identify molecular defects associated with leukemogenesis by utilizing induced pluripotent stem cell (iPSC) technology to model disease progression. We previously derived a patient-specific iPSC line from this family and showed a causative role of RUNX1 in megakaryopoietic defects. Here we report similar results with three additional FPDMM patient-specific iPSC lines including one from a patient who developed MDS. Using a monolayer-based differentiation system, we characterized hematopoietic defects in these cells including immunophenotypic profile of hematopoietic stem and progenitor cells, lineage potential, and megakaryopoietic defects. Furthermore, we aim to induce secondary mutations identified from WES in the MDS patient-specific iPSCs to model disease progression in vitro. Understanding these differences may lead to better tools for assessing leukemic risk and may further define the set of targetable variants for preventative and curative autologous cell therapies.
Scientific Focus Area: Stem Cell Biology
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