Cynthia Guidos, PhD
Developmental & Stem Cell Biology
Flow Cytometry Facility
University of Toronto
Department of Immunology
Phone: 416-813-7654 ext. 305026
Functions of Notch-Fringe Interactions in Lymphocyte Development and Homeostasis
Signaling through several distinct Notch receptors critically regulates lymphocyte development and homeostasis. A hallmark of the Notch pathway is its gene dosage sensitivity, such that small differences in the amount of Notch activity can cause aberrant cell fate choices and T cell leukemia. Fringe proteins are glycosyltransferases that modulate Notch sensitivity to Delta versus Serrate/Jagged ligands in order to restrict Notch activation to discrete times and micro-environmental niches in a variety of developing tissues. The long-term goal of this project is to identify the functions of Notch signaling in the immune system, and to elucidate how Fringe proteins regulate Notch signaling is regulated to ensure proper immune function.
Subversion of Survival and Developmental Pathways in Acute Lymphoblastic Leukemia
(joint projects of Drs. Jayne Danska and Cynthia Guidos)
How do normal hematopoietic cells become abnormal leukemic stem cells? These mechanisms are currently poorly understood, and reflect multiple genetic alterations that perturb proliferation, differentiation, programmed cell death, and self-renewal pathways. The major objective of Drs. Danska and Guidos research program is to identify these disrupted molecular pathways and position this information within the cellular and developmental context of leukemogenesis.
- Canadian Institutes of Health Research (CIHR)
- Cancer Stem Cell Consortium with funding from Genome Canada through the Ontario Genomics Institute & CIHR
- Natural Sciences and Engineering Research Council of Canada
- Ontario Institute of Cancer Research (OICR)
For a complete list of publications, see PubMed
Selected Lymphocyte Development Publications
Yuan JS, Tan JB, Visan I, Matei IR, Urbanellis P, Xu K, Danska JS, Egan SE, Guidos CJ. (2011) Lunatic Fringe prolongs Delta/Notch induced self-renewal of committed αβ T-cell progenitors. Blood. 117(4):1184-1195.
Visan I, Yuan JS, Liu Y, Stanley P, Guidos CJ. (2010) Lunatic Fringe enhances competition for delta-like Notch ligands but does not overcome defective pre-TCR signaling during thymocyte β-selection in vivo. Journal of Immunology. 185(8):4609-4617.
Tan JB, Xu K, Cretegny K, Visan I, Yuan JS, Egan SE, Guidos CJ. (2009) Lunatic and manic fringe co-operatively enhance marginal zone precursor competition for delta-like-1 in splenic endothelial niches. Immunity. 30:254-263. (See also associated Preview in Immunity 30, 175-177).
Visan I, Tan JB, Yuan JS, Harper JA, Koch U, Guidos CJ. (2006) Regulation of T lymphopoiesis by Notch1 and Lunatic fringe-mediated competition for intrathymic niches. Nature Immunology. 7(6):634-43.
Selected Lymphoblastic Leukemia Publications
Ridges, S., Heaton, W.L., Joshi, D., Choi, H., Eiring, A., Batchelor, L., Choudhry, P., Manos, E.J., Sofla, H., Sanati, A., Welborn, S., Agarwal, A., Spangrude, G., Miles, R.R., Cox, J.E., Frazer, J.K., Deininger, M., Balan, K., Sigman, M., Müschen, M., Perova, T., Johnson, R., Montpellier, B., Guidos, C.J., Jones, D., and N.S. Trede. 2012. Zebrafish screen identifies novel compound with selective toxicity against leukemia. Blood 119(24):5621-5631.
Xu, K., Usary, J., Kousis, P.C., Prat, A., Wang, D.Y., Adams, J.R., Wang, W., Loch, A.J., Deng, T., Zhao, W., Cardiff, R.D., Yoon, K., Gaiano, N., Ling, V., Beyene, J., Zacksenhaus, E., Gridley, T., Leong, W.L., Guidos, C.J., Perou, C.M., and S.E. Egan. 2012. Lunatic Fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer. Cancer Cell 21(5):626–641.
Suliman S, Tan J, Xu K, Kousis PC, Kowalski PE, Chang G, Egan S, Guidos CJ. (2011) Notch3 is dispensable for thymocyte β-selection and Notch1-induced T cell leukemogenesis. PLoS ONE. 6(9):e24937.
Guidos C.J.. 2010. "Cryptic" Notch1 messages induce T–ALL. Blood, 116(25):5436-38.
Matei IR, Guidos CJ, Danska JS. (2006) ATM-dependent DNA damage surveillance in T-cell development and leukemogenensis: the DSB connection. Immunological Reviews. 209:142-58.
Gladdy RA, Taylor MD, Williams CJ, Grandal I, Karaskova J, Squire JA, Rutka JT, Guidos CJ, Danska JS. (2003) The RAG-1/2 endonuclease causes genomic instability and controls CNS complications of lymphoblastic leukemia in p53/Prkdc-deficient mice. Cancer Cell. 3(1):37-50.