The characterization of constitutional chromosome translocations in specific types of leukemia has consistently led to an understanding of genes important in leukemogenesis. In some cases this information has been translated to the clinical management of the disease, as well as the reliable identification of structural chromosome rearrangements for the classification of tumors, identification of minimal residual disease after treatment and the prediction of relapse before the onset of symptoms. In particular, the timely identification of the presence of specific rearrangements can often determine the aggressiveness of the treatment regimen which should be used. We have recently characterized the ZNF198/FGFR1 fusion tyrosine kinase gene associated with the highly specific 8;13 translocation which is consistently identified in tumors from patients with an atypical myeloproliferative disease which is associated with T-cell lymphoma and may progress to AML. The involvement of both lineages in this disorder suggests that the structural chromosome rearrangement, which is often the only structural chromosome abnormality in the leukemic cells, occurs in an early progenitor cell before the commitment to the myeloid and lymphoid lineages. This fusion event results in the constitutive activation of the FGFR1 kinase domain through dimerization of the ZNF198 zinc finger motif, which results in mislocalization to the cytoplasm. Genetic studies have implicated a number of leukemia related genes associated with the expression of ZNF198/FGFR1 including PML, ABL, HHR6, SOCS3, SSBP2, SUMO1 and PAI2. To gain a better understanding of the pathways involved in ZNF198/FGFR1 induced leukemogenesis we will use a combination of proteomics and cell and molecular biology approaches to characterize the targets of phosphorylation of this chimeric and extend these studies to three variant, FGFR1 activating rearrangements. We have developed an in vivo model of ZNF198/FGFR1 which produces an MPD-like disease following retroviral transfer of the fusion kinase into primary bone marrow cells using an MSCV based vector. Similar models have been created for the other variant rearrangements. These tumors are transplantable to new hosts. Tumors from these mice will be used to investigate the genetic events that contribute to tumor progression. We will use a series of reagents developed for this project to undertake a series of cellular biology analyses designed to characterize the significance of the dysregulated pathways associated with ZNF198/FGFR1 expression. A deeper insight of the molecular consequences of 6
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