Over the years, research in the lab has focused on gaining an understanding of the role played by transcription factors in mediating the expression of genes that are expressed in the neutrophil maturation pathway. Previous studies from our laboratory have demonstrated defects in mRNA expression of secondary granule protein (SGP) genes and defensins in induced leukemic cell lines, in primary leukemic cells (AML), in myelodysplasia (MDS) and in a rare inherited disorder termed Specific granule deficiency (SGD). These observations supported the hypothesis that neutrophil SGP gene expression is regulated at the level of transcription. We have therefore sought to elucidate the molecular basis for SGD both to provide insight into the regulation of normal neutrophil specific gene expression and as an entry point for the study of transcriptional dysregulation in premalignant and malignant myeloid disorders.
In more recent studies, we have modeled bone marrow failure syndromes including Diamond Blackfan Anemia (DBA) and 5q- MDS in zebrafish. Haploinsufficiency of ribosomal proteins have been shown to be causitive in both these diseases. In an attempt to determine the mechanism underlying these "ribosomeopathies" we have shown that both p53 -dependent and p53-independent pathways play a role in the manifestation of the cell death and anemia associated with both diseases. Ongoing studies have begun to identify the molecular pathways affected as a result of the ribosomal stress caused by ribosomal protein haploinsufficiency.