- Myelodysplastic syndromes and myeloid malignancies
- Innate immune signaling in vascular and hematopoietic function
- Genomics for clinical diagnostics
My lab focuses on two major areas: (1) Understanding the molecular basis of myeloid malignancies, in particular the preleukemic bone marrow failure conditions called myelodysplastic syndromes (MDS); and (2) Determining the role of the endothelium in the development of the hematopoietic system. With respect to both areas we have been studying the role of two pathways: innate immune signaling as represented by the Toll-like receptor (TLR) pathways, and the Notch signaling pathway.
With respect to the myeloid malignancies, we have a major focus on understanding the relationship of non-coding RNAs and the regulation of the epigenome. We have taken genomic approaches to study patient material followed by functional analyses of specific microRNAs. One example of translation of genomic studies to understanding biologic function is our discovery that microRNAs residing on the long arm of chromosome 5 act to independently regulate innate immune signaling DNA methylation. Deletion of chromosome arm 5q is the commonest structural anomaly seen in MDS, and current studies centre around establishing the function of these microRNAs, deregulated innate immune signaling and remodeling of the epigenome in the manifestations of MDS. We are using a variety of in vivo transplantation assays, in vitro cell biology and cell signaling studies as well as additional genomic approaches to answer these questions.
In separate work related to innate immune signaling, we have identified a novel protein, Sash1, by differential proteomic analysis that acts as a scaffold protein in the TLR signal transduction pathway. Expression analyses indicate that this molecule is highly expressed in the microvasculature. Molecular and cellular studies to elucidate the mechanisms of action of this protein are ongoing. As well we have generated a gene-targeted mouse model that demonstrates that loss of this protein results in perinatal death. Currently, we are generating a conditional gene-targeted mouse model to gain a better understanding of the physiologic role of Sash1.
Over the last few years my clinical interest has shifted to using genomics methodologies to deliver clinical diagnostic testing. We were the first accredited lab in Canada to use next-generation sequencing techniques to deliver clinical testing. We are currently developing various gene panels as well as genome-wide tests with the intention of taking these into the clinic.
Kulic I, Robertson G, Chang L, Baker JH, Lockwood WW, Mok W, Fuller M, Fournier M, Wong N, Chou V, Robinson MD, Chun HJ, Gilks B, Kempkes B, Thomson TA, Hirst M, Minchinton AI, Lam WL, Jones S, Marra M, Karsan A. Loss of the Notch effector RBPJ promotes tumorigenesis. J Exp Med. 2015 Jan 12;212(1):37-52. doi: 10.1084/jem.20121192. Epub 2014 Dec 15.
Bosdet IE, Docking TR, Butterfield YS, Mungall AJ, Zeng T, Coope RJ, Yorida E, Chow K, Bala M, Young SS, Hirst M, Birol I, Moore RA, Jones SJ, Marra MA, Holt R, Karsan A. A Clinically Validated Diagnostic Second-Generation Sequencing Assay for Detection of Hereditary BRCA1 and BRCA2 Mutations. J Mol Diagn. 2013 Sep 25. pii: S1525-1578(13)00135-9. doi: 10.1016/j.jmoldx.2013.07.004.
Dauphinee SM, Clayton A, Hussainkhel A, Yang C, Park YJ, Fuller ME, Blonder J, Veenstra TD, Karsan A. SASH1 is a scaffold molecule in endothelial TLR4 signaling. J Immunol. 2013 Jul 15;191(2):892-901. doi: 10.4049/jimmunol.1200583. Epub 2013 Jun 17.
Chang L, Noseda M, Higginson M, Ly M, Patenaude A, Fuller M, Kyle AH, Minchinton AI, Puri MC, Dumont DJ, Karsan A. Differentiation of vascular smooth muscle cells from local precursors during embryonic and adult arteriogenesis requires Notch signaling. Proc Natl Acad Sci U S A. 2012 May 1;109(18):6993-8. Epub 2012 Apr 16. PubMed PMID: 22509029; PubMed Central PMCID: PMC3345008. Author's final copy
Chang AC, Fu Y, Garside VC, Niessen K, Chang L, Fuller M, Setiadi A, Smrz J, Kyle A, Minchinton A, Marra M, Hoodless PA, Karsan A. Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase. Dev Cell. 2011 Aug 16;21(2):288-300
Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A, Hirst M, Hogge D, Marra M, Wells RA, Buckstein R, Lam W, Humphries RK, Karsan A. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med. 2010 Jan;16(1):49-58. Epub 2009 Nov 8.Authors Proof