Chromatin remodeling proteins regulate DNA transcription, replication, repair and methylation, thereby providing a molecular link that is central to understanding cell growth and differentiation of normal and neoplastic cells. We identified a novel member of the SNF2 family of chromatin modifying proteins, which we termed Proliferation Associated SNF2-like Gene (PASG), from a leukemia cell line. We further generated a PASG hypomorphic mutant mouse model characterized by genomic hypomethylation, decreased stem cell expansion, replicative senescence, altered gene transcription, developmental growth retardation and a premature aging phenotype. Fibroblasts derived from these PASG mutant embryos also undergo accelerated replicative senescence associated with distinctive DNA methylation and gene expression changes as well as chromosome instability. The senescence phenotype can be circumvented by expression of oncogenic viral proteins as well as by exposure to specific cytokines, suggesting pathways for malignant transformation in the setting of epigenetically-mediated senescence. We have also identified an in-frame deletion variant of PASG in a high percentage of acute leukemias that removes one of the conserved, SNF functional domains called STRAGGL. This deletion variant loses its ability to facilitate DNA methylation and to interact with DNA methyltransferases, thus suggesting that it may function in a dominant negative fashion. Preliminary data further suggests that this deletion variant is associated with a poor outcome, complex karyotypes and distinct RNA expression patterns in acute myelogenous leukemia. These results have led us to hypothesize that PASG functions as a key protein contributing to normal genomic epigenetic patterning and gene expression, chromosome stability and expansion of progenitor cells through the inhibition of replicative senescence. We are now proposing to 1) identify the structural-functional relationships of wild type and variant forms of PASG critical for facilitation of DNA methyltransferase- mediated DNA methylation;2) test the hypothesis that the deletion variant of PASG observed in leukemia can alter epigenetic patterning in somatic cells during myelopoiesis and contribute to the development and behavior of leukemia;3) determine the frequency and expression level of wild type and mutant forms of PASG in acute leukemias and whether they are associated with altered epigenetic and gene expression patterns as well as clinical outcomes. These studies should provide significant information concerning mechanisms of epigenetic patterning and gene expression in normal hematopoiesis and leukemia as well as in risk-group and epigenetically-directed therapies.
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