The long-term objectives of this project address the molecular pathogenesis of leukemia's that harbor mutations of the HRX (MLL, ALL1) gene due to acquired translocations of chromosome band 11q23. HRX comprises a distinctive and new category of oncogene that codes for proteins implicated to function epigenetically in gene regulation through effects on the regional organization of chromatin domains. The studies in this application will explore the possibility that HRX modulates the formation of silencing heterochromatin complexes on critical subordinate genes and whether mutations of HRX in leukemia create fusion proteins that function as constitutive transcriptional activators to circumvent epigenetic constraints on cellular growth control. The studies proposed in Aim #1 will employ in vitro transformation models to investigate the oncogenic mechanisms underlying HRX fusion proteins. These studies will determine if transcriptional activation is a consistent requirement for their oncogeneic properties or if diverse effector mechanisms may confer similar pathogenetic consequences. The role of HRX fusion partners in determining the lineage derivation of 11q23 leukemia's will be determined. Transcriptional perturbations that are maintained in leukemic hematopoietic progenitors will be investigated using conditionally transforming alleles of HRX chimeric genes. A genetic approach will identify genes that collaborate with HRX in leukemogenesis in bone marrow cells from BXH-2 mice that are highly prone to myeloid leukemia's. The functions of wild type HRX will be addressed in Aim #2 by studying the anti-phosphatase Sbf1, a newly discovered oncoprotein that interacts with the carboxy-terminal SET domain of HRX. The ability of Sbf1 to modulate the molecular effector functions of HRX and other SET domain proteins through changes in phosphorylation will be addressed using biochemical and genetic techniques. The role of Sbf1 in normal growth and development will be studied in Sbf1 nullizygous mice.
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