We have awarded a three year, $600,000 grant to our Scientific Director, Dr. Nancy A. Speck, University of Pennsylvania, for a research project entitled ‘Mouse Models of Secondary Mutations in FPD/AML". Dr. Speck is developing a mouse model of FPD/AML by introducing mutations into the Runx1 gene that lower the effective RUNX1 dosage in the mouse. She proposes to use this model to test which secondary mutations found in MDS and AML are the most potent at driving clonal hematopoietic stem cell expansion and leukemia in the context of lower levels of RUNX1. This study will complement the planned longitudinal sequencing study of secondary mutations in FPD/AML patients that the RRP is planning to launch in the near future, and also the efforts by Dr. Zon’s and Dr. Majeti’s laboratories to develop human xenograft and zebrafish models. Knowing which acquired mutations behave most aggressively to promote hematopoietic stem cell expansion and leukemia will help physicians decide how early to intervene if a patient has evidence of clonal hematopoiesis. The FPD/AML mouse model will be made available to other investigators who wish to test the activity of drugs to delay, prevent, or reverse clonal hematopoietic stem cell expansion associated with acquired mutations.