MOUSE MODELS FOR FAMILIAL PLATELET DISORDER

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Mutations in the RUNX1 gene (also known as AML1) cause a rare familial platelet disorder with propensity to develop acute myelogenous leukemia (FPD/AML). FPD/AML patients have reduced platelet numbers, defects in platelet function, and decreased numbers of hematopoietic progenitors in their bone marrow and peripheral blood. FPD/AML patients also have a propensity to progress to acute myelogenous leukemia. The mutations found in FPD/AML pedigrees involve only one copy of the RUNX1 gene. RUNX1 encodes a DNA-binding subunit of the heterodimeric core-binding factors (CBFs). The "Runt" domain in Runx1 mediates DNA-binding and heterodimerization with the non-DNA-binding CBFbeta subunit. Mutations in FPD/AML patients include missense and nonsense mutations in the Runt domain, creation of a cryptic splice acceptor site within the Runt domain, and an intragenic deletion. Biallelic point mutations in the Runx1 Runt domain were also recently documented in approximately 25% of M-0, AML, defining a new subgroup in this disease. The similar clinical phenotypes of FPD/AML patients suggest that haploinsufficiency is the underlying mechanism in all cases of the disease. However, the severity of platelet defects in FPD/AML families varies, suggesting that subtle phenotypic variation may be conferred by the different FPD/AML RUNX1 alleles. The goals of this project are to understand how mutations found in the Runx1 Runt domain in FPD/AML and AML M-0, patients affect the functions of the Runx1 protein, both in vitro and in vivo. The Specific Aims are: 1. Determine how mutations in the Runx1 Runt domain found in FPD/AML and M-0, AML patients affect DNA-binding, CBFP heterodimerization, and the Runt domain structure. 2. Determine whether point mutations in the Runx1 Runt domain found in FPD/AML patients result in haploinsufficiency, in the generation of partially functional Runx1 alleles, or in transdominant negative Runx1 alleles. 3. Generate and characterize mouse models for FPD/AML that mimic the hematopoietic progenitor defects, platelet defects, and propensity for AML.