About

Aly Karsan, MD, FRCPC
Associate Member

• Mecial Director, Cancer Genetics Laboratory
• Head, Clinical Diagnostic Genomics, Genome Sciences Centre, BC Cancer Agency
• Professor, Pathology and Laboratory Medicine, University of British Columbia (UBC)

Research Interests

• Myelodysplastic syndromes
• Innate immune signaling in vascular and hematopoietic function
• Role of Notch in cardiovascular development and angiogenesis

My lab focuses on two major areas: (1) Understanding the molecular basis of 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.

We have recently demonstrated that microRNAs that reside on the long arm of chromosome 5 act to regulate innate immune signaling. Deletion of chromosome arm 5q is the commonest structural anomaly seen in MDS, and our current work is centred around establishing the function of these microRNAs and deregulated innate immune signaling 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 genomic approaches to answer these questions.

In other work related to innate immune signaling, we have identified a novel protein by differential proteomic analysis that appears to act as a scaffold protein in a MyD88-independent 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 is incompatible with life past mid-gestation. Currently, we are generating a conditional gene-targeted mouse model to gain a better understanding of the physiologic role of this protein.

My lab has also had a long-standing interest in the role of Notch signaling in the endothelium. We have generated a conditional, inducible mouse model in which we are able to regulate Notch signaling. Using this and other models we are studying how endothelial cells contribute to hematopoietic development both at the initial stages of intraembryonic hematopoiesis where hematopoietic stem cells are thought to derive from the endothelium, as well as during fetal liver and adult hematopoiesis, where the endothelium may act as a niche to regulate stem cell self renewal and/or differentiation.

Publications

Selected Publications

2009

Fu Y, Chang A, Chang L, Niessen K, Eapen S, Setiadi A, & Karsan A. Differential regulation of TGFbeta signaling pathways by notch in human endothelial cells. J Biol Chem, 2009.   View Abstract

Vercauteren SM, Bashashati A, Wu D, Brinkman RR, Eaves C, Eaves A, & Karsan A. Reduction in multi-lineage and erythroid progenitors distinguishes myelodysplastic syndromes from non-malignant cytopenias. Leuk Res, 2009. View Abstract

2008

Starczynowski DT, Vercauteren S, Telenius A, Sung S, Tohyama K, Brooks-Wilson  A, Spinelli JJ, Eaves CJ, Eaves AC, Horsman DE, Lam WL, Karsan A.  High-resolution whole genome tiling path array CGH analysis of CD34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival. Blood. 2008 Oct 15;112(8):3412-24. View Abstract

Niessen K, Fu Y, Chang L, Hoodless PA, McFadden D, Karsan A.  Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J Cell Biol. 2008 Jul 28;182(2):315-25. View Abstract

Karsan A. Notch and integrin affinity: a sticky situation. Sci Signal 1 (2): pe2, 2008.  View Abstract

Niessen K, & Karsan A. Notch signaling in cardiac development. Circ Res 102 (10): 1169-81, 2008. Toll-free link to full text

Wu C, Cipollone J, Maines-Bandiera S, Tan C, Karsan A, Auersperg N, & Roskelley CD. The morphogenic function of E-cadherin-mediated adherens junctions in epithelial ovarian carcinoma formation and progression. Differentiation 76 (2): 193-205, 2008. View Abstract

2007

Larrivee B, & Karsan A. Involvement of marrow-derived endothelial cells in vascularization. Handb Exp Pharmacol  (180): 89-114, 2007. View Abstract

Leong KG, Niessen K, Kulic I, Raouf A, Eaves C, Pollet I, & Karsan A. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med 204 (12): 2935-48, 2007. View Abstract

Niessen K, & Karsan A. Notch signaling in the developing cardiovascular system. Am J Physiol Cell Physiol 293 (1): C1-11, 2007. Toll-free link to full text

Zhande R, Dauphinee SM, Thomas JA, Yamamoto M, Akira S, & Karsan A. FADD negatively regulates lipopolysaccharide signaling by impairing interleukin-1 receptor-associated kinase 1-MyD88 interaction. Mol Cell Biol 27 (21): 7394-404, 2007. View Abstract

Zhande R, & Karsan A. Erythropoietin promotes survival of primary human endothelial cells through PI3K-dependent, NF-kappaB-independent upregulation of Bcl-xL. Am J Physiol Heart Circ Physiol 292 (5): H2467-74, 2007. View Abstract

2006

Dauphinee SM, & Karsan A. Lipopolysaccharide signaling in endothelial cells. Lab Invest 86 (1): 9-22, 2006. View Abstract

Larrivee B, Olive PL, & Karsan A. Tissue distribution of endothelial cells in vivo following intravenous injection. Exp Hematol 34 (12): 1741-5, 2006. View Abstract

Leong KG, & Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood 107 (6): 2223-33, 2006. View Abstract

Murphy S, Larrivee B, Pollet I, Craig KS, Williams DE, Huang XH, Abbott M, Wong F, Curtis C, Conrads TP, Veenstra T, Puri M, Hsiang Y, Roberge M, Andersen RJ, & Karsan A. Identification of sokotrasterol sulfate as a novel proangiogenic steroid. Circ Res 99 (3): 257-65, 2006. View Abstract

Noseda M, Fu Y, Niessen K, Wong F, Chang L, McLean G, & Karsan A. Smooth Muscle alpha-actin is a direct target of Notch/CSL. Circ Res 98 (12): 1468-70, 2006. View Abstract

Noseda M, & Karsan A. Notch and minichromosome maintenance (MCM) proteins: integration of two ancestral pathways in cell cycle control. Cell Cycle 5 (23): 2704-9, 2006. View Abstract

 2005

Harfouche R, Malak NA, Brandes RP, Karsan A, Irani K, & Hussain SN. Roles of reactive oxygen species in angiopoietin-1/tie-2 receptor signaling. Faseb J 19 (12): 1728-30, 2005. View Abstract

Hood BL, Lucas DA, Kim G, Chan KC, Blonder J, Issaq HJ, Veenstra TD, Conrads TP, Pollet I, & Karsan A. Quantitative analysis of the low molecular weight serum proteome using 18O stable isotope labeling in a lung tumor xenograft mouse model. J Am Soc Mass Spectrom 16 (8): 1221-30, 2005. View Abstract

Karsan A. The role of notch in modeling and maintaining the vasculature. Can J Physiol Pharmacol 83 (1): 14-23, 2005. View Abstract

Karsan A, Blonder J, Law J, Yaquian E, Lucas DA, Conrads TP, & Veenstra T. Proteomic analysis of lipid microdomains from lipopolysaccharide-activated human endothelial cells. J Proteome Res 4 (2): 349-57, 2005. View Abstract

Karsan A, Eigl BJ, Flibotte S, Gelmon K, Switzer P, Hassell P, Harrison D, Law J, Hayes M, Stillwell M, Xiao Z, Conrads TP, & Veenstra T. Analytical and preanalytical biases in serum proteomic pattern analysis for breast cancer diagnosis. Clin Chem 51 (8): 1525-8, 2005. View Abstract

Karsan A, Pollet I, Yu LR, Chan KC, Conrads TP, Lucas DA, Andersen R, & Veenstra T. Quantitative proteomic analysis of sokotrasterol sulfate-stimulated primary human endothelial cells. Mol Cell Proteomics 4 (2): 191-204, 2005. View Abstract

Larrivee B, & Karsan A. Isolation and culture of primary endothelial cells. Methods Mol Biol 290: 315-29, 2005. View Abstract

Larrivee B, Niessen K, Pollet I, Corbel SY, Long M, Rossi FM, Olive PL, & Karsan A. Minimal contribution of marrow-derived endothelial precursors to tumor vasculature. J Immunol 175 (5): 2890-9, 2005. View Abstract

Larrivee B, Pollet I, & Karsan A. Activation of vascular endothelial growth factor receptor-2 in bone marrow leads to accumulation of myeloid cells: role of granulocyte-macrophage colony-stimulating factor. J Immunol 175 (5): 3015-24, 2005. View Abstract

Noseda M, Niessen K, McLean G, Chang L, & Karsan A. Notch-dependent cell cycle arrest is associated with downregulation of minichromosome maintenance proteins. Circ Res 97 (2): 102-4, 2005. View Abstract

2004

MacKenzie F, Duriez P, Larrivee B, Chang L, Pollet I, Wong F, Yip C, & Karsan A. Notch4-induced inhibition of endothelial sprouting requires the ankyrin repeats and involves signaling through RBP-Jkappa. Blood 104 (6): 1760-8, 2004. View Abstract

MacKenzie F, Duriez P, Wong F, Noseda M, & Karsan A. Notch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and -independent pathways. J Biol Chem 279 (12): 11657-63, 2004. View Abstract

Noseda M, Chang L, McLean G, Grim JE, Clurman BE, Smith LL, & Karsan A. Notch activation induces endothelial cell cycle arrest and participates in contact inhibition: role of p21Cip1 repression. Mol Cell Biol 24 (20): 8813-22, 2004. View Abstract

Noseda M, McLean G, Niessen K, Chang L, Pollet I, Montpetit R, Shahidi R, Dorovini-Zis K, Li L, Beckstead B, Durand RE, Hoodless PA, & Karsan A. Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation. Circ Res 94 (7): 910-7, 2004. View Abstract

Wong F, Hull C, Zhande R, Law J, & Karsan A. Lipopolysaccharide initiates a TRAF6-mediated endothelial survival signal. Blood 103 (12): 4520-6, 2004. View Abstract

 2003

Harfouche R, Gratton JP, Yancopoulos GD, Noseda M, Karsan A, & Hussain SN. Angiopoietin-1 activates both anti- and proapoptotic mitogen-activated protein kinases. Faseb J 17 (11): 1523-5, 2003. View Abstract

Larrivee B, Lane DR, Pollet I, Olive PL, Humphries RK, & Karsan A. Vascular endothelial growth factor receptor-2 induces survival of hematopoietic progenitor cells. J Biol Chem 278 (24): 22006-13, 2003. View Abstract

Pollet I, Opina CJ, Zimmerman C, Leong KG, Wong F, & Karsan A. Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-kappaB and c-Jun N-terminal kinase. Blood 102 (5): 1740-2, 2003. View Abstract

2002

Hull C, McLean G, Wong F, Duriez PJ, & Karsan A. Lipopolysaccharide signals an endothelial apoptosis pathway through TNF receptor-associated factor 6-mediated activation of c-Jun NH2-terminal kinase. J Immunol 169 (5): 2611-8, 2002. View Abstract

Leong KG, Hu X, Li L, Noseda M, Larrivee B, Hull C, Hood L, Wong F, & Karsan A. Activated Notch4 inhibits angiogenesis: role of beta 1-integrin activation. Mol Cell Biol 22 (8): 2830-41, 2002. View Abstract

Levkau B, Kenagy RD, Karsan A, Weitkamp B, Clowes AW, Ross R, & Raines EW. Activation of metalloproteinases and their association with integrins: an auxiliary apoptotic pathway in human endothelial cells. Cell Death Differ 9 (12): 1360-7, 2002. View Abstract

Litwin C, Leong KG, Zapf R, Sutherland H, Naiman SC, & Karsan A. Role of the microenvironment in promoting angiogenesis in acute myeloid leukemia. Am J Hematol 70 (1): 22-30, 2002. View Abstract

Zheng X, Karsan A, Duronio V, Chu F, Walker DC, Bai TR, & Schellenberg RR. Interleukin-3, but not granulocyte-macrophage colony-stimulating factor and interleukin-5, inhibits apoptosis of human basophils through phosphatidylinositol 3-kinase: requirement of NF-kappaB-dependent and -independent pathways. Immunology 107 (3): 306-15, 2002. View Abstract

2001

Churg A, Dai J, Zay K, Karsan A, Hendricks R, Yee C, Martin R, MacKenzie R, Xie C, Zhang L, Shapiro S, & Wright JL. Alpha-1-antitrypsin and a broad spectrum metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects. Lab Invest 81 (8): 1119-31, 2001. View Abstract

Imanishi T, Hano T, Nishio I, Han DK, Schwartz SM, & Karsan A. Apoptosis of vascular smooth muscle cells is induced by Fas ligand derived from endothelial cells. Jpn Circ J 65 (6): 556-60, 2001. View Abstract

Roskelley CD, Williams DE, McHardy LM, Leong KG, Troussard A, Karsan A, Andersen RJ, Dedhar S, & Roberge M. Inhibition of tumor cell invasion and angiogenesis by motuporamines. Cancer Res 61 (18): 6788-94, 2001. View Abstract

2000

Duriez PJ, Wong F, Dorovini-Zis K, Shahidi R, & Karsan A. A1 functions at the mitochondria to delay endothelial apoptosis in response to tumor necrosis factor. J Biol Chem 275 (24): 18099-107, 2000. View Abstract

Larrivee B, & Karsan A. Signaling pathways induced by vascular endothelial growth factor (review). Int J Mol Med 5 (5): 447-56, 2000. View Abstract

Leong KG, & Karsan A. Signaling pathways mediated by tumor necrosis factor alpha. Histol Histopathol 15 (4): 1303-25, 2000. View Abstract

1999

Schwartz BR, Karsan A, Bombeli T, & Harlan JM. A novel beta 1 integrin-dependent mechanism of leukocyte adherence to apoptotic cells. J Immunol 162 (8): 4842-8, 1999. View Abstract

Stempien-Otero A, Karsan A, Cornejo CJ, Xiang H, Eunson T, Morrison RS, Kay M, Winn R, & Harlan J. Mechanisms of hypoxia-induced endothelial cell death. Role of p53 in apoptosis. J Biol Chem 274 (12): 8039-45, 1999. View Abstract

Zen K, Karsan A, Stempien-Otero A, Yee E, Tupper J, Li X, Eunson T, Kay MA, Wilson CB, Winn RK, & Harlan JM. NF-kappaB activation is required for human endothelial survival during exposure to tumor necrosis factor-alpha but not to interleukin-1beta or lipopolysaccharide. J Biol Chem 274 (40): 28808-15, 1999. View Abstract

1998

Choi KB, Wong F, Harlan JM, Chaudhary PM, Hood L, & Karsan A. Lipopolysaccharide mediates endothelial apoptosis by a FADD-dependent pathway. J Biol Chem 273 (32): 20185-8, 1998. View Abstract

Chuang PI, Yee E, Karsan A, Winn RK, & Harlan JM. A1 is a constitutive and inducible Bcl-2 homologue in mature human neutrophils. Biochem Biophys Res Commun 249 (2): 361-5, 1998. View Abstract

Hu X, Yee E, Harlan JM, Wong F, & Karsan A. Lipopolysaccharide induces the antiapoptotic molecules, A1 and A20, in microvascular endothelial cells. Blood 92 (8): 2759-65, 1998. View Abstract

Karsan A, Cornejo CJ, Winn RK, Schwartz BR, Way W, Lannir N, Gershoni-Baruch R, Etzioni A, Ochs HD, & Harlan JM. Leukocyte Adhesion Deficiency Type II is a generalized defect of de novo GDP-fucose biosynthesis. Endothelial cell fucosylation is not required for neutrophil rolling on human nonlymphoid endothelium. J Clin Invest 101 (11): 2438-45, 1998. View Abstract

Mitra D, Kim J, MacLow C, Karsan A, & Laurence J. Role of caspases 1 and 3 and Bcl-2-related molecules in endothelial cell apoptosis associated with thrombotic microangiopathies. Am J Hematol 59 (4): 279-87, 1998. View Abstract

Zen K, Karsan A, Eunson T, Yee E, & Harlan JM. Lipopolysaccharide-induced NF-kappaB activation in human endothelial cells involves degradation of IkappaBalpha but not IkappaBbeta. Exp Cell Res 243 (2): 425-33, 1998. View Abstract

1997

Bombeli T, Karsan A, Tait JF, & Harlan JM. Apoptotic vascular endothelial cells become procoagulant. Blood 89 (7): 2429-42, 1997. View Abstract

Karsan A, Yee E, Poirier GG, Zhou P, Craig R, & Harlan JM. Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms. Am J Pathol 151 (6): 1775-84, 1997. View Abstract

Pang XP, Hershman JM, & Karsan A. TNF-alpha induction of A1 expression in human cancer cells. Oncol Res 9 (11-12): 623-7, 1997. View Abstract

Slowik MR, Min W, Ardito T, Karsan A, Kashgarian M, & Pober JS. Evidence that tumor necrosis factor triggers apoptosis in human endothelial cells by interleukin-1-converting enzyme-like protease-dependent and -independent pathways. Lab Invest 77 (3): 257-67, 1997. View Abstract

1996

Karsan A, & Harlan JM. Modulation of endothelial cell apoptosis: mechanisms and pathophysiological roles. J Atheroscler Thromb 3 (2): 75-80, 1996. View Abstract

Karsan A, Yee E, & Harlan JM. Endothelial cell death induced by tumor necrosis factor-alpha is inhibited by the Bcl-2 family member, A1. J Biol Chem 271 (44): 27201-4, 1996. View Abstract

Karsan A, Yee E, Kaushansky K, & Harlan JM. Cloning of human Bcl-2 homologue: inflammatory cytokines induce human A1 in cultured endothelial cells. Blood 87 (8): 3089-96, 1996. View Abstract

Lab People

Postdoctoral Fellow Dr. YangXin Fu Dr. Michèle Fournier Dr. Jeremy Parker Dr. Alex Patenaude Dr. Dan Starczynowski Dr. Suzanna Vercautern Dr. Joanna Wegrzyn Dr. Nelson Wong

Graduate Students Alex Chang Linda Chang Shauna Dauphinee Angela Hussainkhel Rawa Ibrahim Iva Kulic Jeffrey Lam Kate Slowski

Other members Megan Abbott Michelle Higginson Michelle Ly Sandy Sung Fred Wong

Open Positions

Inquiries welcome.