PROFESSOR
M.D., FRCPC
Academic and Clinical Interests
My main academic and clinical interests are in diagnostic hematopathology and translational research related to this discipline. Together with Ron Geyer from the Department of Biochemistry, I co-direct the Genomic Medicine and Pathobiology Research Group (G-MAP). This is a multi-disciplinary team comprising researchers with expertise in Pathology, Biochemistry and Cellular Biology, Medical and Surgical Oncology, and Computer Science that aims to clarify molecular mechanisms of disease promotion and progression using innovative genomic and proteomics technologies. Ultimately, G-MAP research aims to improve patient diagnosis, treatment, and survival by refining pathology classifications of disease, by developing novel prognostic and predictive markers to guide therapy decisions, and by identifying new targets suitable for the development of novel therapeutic interventions.
State of the art genomics infrastructure obtained through Canada Foundation for Innovation supports G-MAP research. This infrastructure includes: a Beckman Elite-ESP Cell Sorter, MACS Magnetic Bead Separators, a Ciphergen Protein Chip (SELDI/MS) System, a Beckman Biomek 2000 Laboratory Robotic Workstation, a Waters 3 Dimensional LC/ESI-TOF MS System, an Axon GenePix microarray scanner, and an ABI Prism 310 DNA Sequencer located at the Saskatoon Cancer Centre. Extensive bioinformatics infrastructure is accessed through Tony Kusalik in the Dept of Computer Science and G-MAP has established collaborations with Andrew Ross, from the Bioanalytical Mass Spectrometry Unit at the NRC Plant Biotechnology Institute. Important pathology tools including a tissue microarrayer, an automated immunohistochemical stainer dedicated for research, and a laser capture microdissector are also available through Dr. Tony Magliocco at the University of Calgary.
Research Interests Saskatoon Cancer Research Unit
My research program focuses on epigenetic silencing of key tumor suppressor genes in acute myeloid leukemia (AML) pathogenesis and characterization of the IGF-1 signaling pathway in the evolution of chronic myelogenous leukemia (CML) blast crisis.
Using chromatin immunoprecipitation (ChIP) and promoter methylation mapping by temporal temperature gradient gel electrophoresis, we found that the DNA demethylating agent decitabine relieves p21WAF1 repression by a mechanism involving release of histone deacetylase 1 (HDAC1) without requiring p21WAF1 promoter demethylation. This observation has important implications for understanding the therapeutic efficacy of this agent. We recently provided the first evidence that zebularine, an oral administered demethylating agent, potently induces apotosis and activates silenced p15 in acute myeloid leukemia cell lines and purified patient blasts. Current work in this area is characterizing the role of the histone methyltransferase SUV39H1 in silencing p15 and p21 in AML.
In collaboration with Ron Geyer and Wei-Feng Dong, my lab discovered that RIZ1, a histone methylatransferase gene, exerts tumor suppressor properties in CML blast crisis by regulating an IGF-1 autocrine growth pathway. Several RIZ1-regulated genes involved in IGF-1 signaling were identified using high-density cDNA microarrays and RIZ-1 was found to associate with the promoter regions of IGF-1 and to increase histone H3 lysine 9 methylation by ChIP assays. Disruption of autocrine IGF-1 signaling decreased the viability of blast crisis cells and forced RIZ-1 expression in these cells decreased RIZ-1 receptor activation and activation of downstream signaling components ERK 1/2 and AKT. These results highlight the therapeutic potential of inhibiting the IGF-1 pathway in the acute, treatment resistant phase of CML. My lab is now actively working with Ron Geyer’s lab to investigate cross talk between the BCR-ABL and IGF-1 signaling pathways in human CML cells and mouse models we are developing. Another major project is now underway to generate novel peptide aptamers capable of blocking the functional domains of the BCR-ABL.
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