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.
| Soung, Do Y; Talebian, Laleh; Matheny, Christina J et al. (2012) Runx1 dose-dependently regulates endochondral ossification during skeletal development and fracture healing. J Bone Miner Res 27:1585-97 |
| Matheny, Christina J; Speck, Maren E; Cushing, Patrick R et al. (2007) Disease mutations in RUNX1 and RUNX2 create nonfunctional, dominant-negative, or hypomorphic alleles. EMBO J 26:1163-75 |
| Li, Zhe; Yan, Jiangli; Matheny, Christina J et al. (2003) Energetic contribution of residues in the Runx1 Runt domain to DNA binding. J Biol Chem 278:33088-96 |
| Zhang, Lina; Lukasik, Stephen M; Speck, Nancy A et al. (2003) Structural and functional characterization of Runx1, CBF beta, and CBF beta-SMMHC. Blood Cells Mol Dis 30:147-56 |
| Speck, N A (2001) Core binding factor and its role in normal hematopoietic development. Curr Opin Hematol 8:192-6 |
