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Susan Winandy, PhD

TitleAssistant Professor
InstitutionBoston University School of Medicine
DepartmentPathology & Laboratory Medicine
Address670 Albany St Biosquare III
Boston MA 02118
Phone(617) 414-7090
ORCID ORCID Icon0000-0003-3096-070X
Other Positions
TitleGraduate Faculty (Primary Mentor of Grad Students)
InstitutionBoston University School of Medicine, Division of Graduate Medical Sciences

 Research Expertise & Professional Interests
We are interested in understanding the molecular pathways underlying normal blood cell development and how, when these pathways are deregulated, leukemia can result. Our studies focus on the role of the nuclear protein Ikaros in both normal and abnormal blood cell development. Ikaros is a transcriptional regulatory protein that can act as both an activator and a repressor. It is expressed almost exclusively in cells of the hematopoietic lineage and is required for normal development of all blood cell lineages. In addition, mutation of Ikaros leads to T cell leukemia in genetically engineered Ikaros mutant mouse models. Because Ikaros is highly conserved (95% identity at the amino acid level in mice and humans), studies performed to understand Ikaros functions in mice will almost certainly translate to understanding its role in human cells. We have focused our studies on defining the role of Ikaros in T cell development and function as well as on how Ikaros acts as a tumor suppressor. A summary of some of the research areas we are pursuing and questions we are asking is highlighted below.

1) Ikaros and Notch: Interplay during T cell development and leukemogenesis

Ikaros is a tumor suppressor for the lymphocyte lineage in mice. 100% of mice with a genetically engineered mutation in the Ikaros gene (Ikaros null mice) develop T cell leukemia. Importantly, mutations in Ikaros also are found in human leukemia. High levels of non-DNA binding (dominant-negative) Ikaros isoforms have been observed in leukemic cells from children with T- and B-Acute Lymphoblastic Leukemia (ALL). More recently, mutations in IKZF1, the gene encoding Ikaros, were identified as a strong predictor of increased likelihood of relapse in children with B-ALL and as a common genetic lesion in Philadelphia chromosome-positive adult ALL. The Notch receptor is a transmembrane protein that, like Ikaros, plays an important role in T cell development in the thymus. Notch function is regulated through two proteolytic cleavage events that occur upon recognition of its extracellular ligand. These cleavages free the intracellular domain, which travels to the nucleus. Here, intracellular Notch regulates transcription of Notch target genes through its binding to and activation of the DNA-binding factor RBP-Jk. Mutations in Notch that result in its constitutive activation have also been identified in human ALL. We have shown that Ikaros is required for transcriptional repression of Notch target genes in developing thymocytes and leukemia cells, and hypothesized that this may contribute to Ikaros’ mechanistic role as a tumor suppressor. We are characterizing the importance of this interaction to the leukemogenic process in Ikaros null mice and are interested in understanding how RBP-Jk and Ikaros coordinate Notch target gene repression vs. activation during normal T cell development.

2) Ikaros regulates peripheral T cell differentiation and cytokine gene expression

CD4+ helper T (Th) cells are important mediators of the immune response through their regulated production of cytokines. Naive CD4+ Th cells differentiate during the course of an immune response to secrete cytokines tailored to promote eradication of the specific pathogenic assault. Two well-studied CD4+ T cell effector subsets, Th1 and Th2 cells, are defined by their ability to secrete the cytokines IFNg? and IL-4, respectively. Th1 responses are most effective against intracellular pathogens such as viruses whereas Th2 cells protect against extracellular pathogens including bacteria and fungi. A third subset of CD4+ T cells, called regulatory T cells, are critical for controlling both normal and abnormal (autoimmune) T cell responses. Expression of IL-10 and TGF-b by these cells contributes to these roles. In the absence of Ikaros, T cells are unable to develop into the Th2 lineage, but rather default to the Th1 lineage. In addition, Ikaros has been defined as a regulator of many cytokine genes including IlL-2, IL-4, IFN-g and IL-10. These data suggest that Ikaros is crucial for shaping the course of an immune response. Future studies will include testing this hypothesis during the course of an in vivo immune response as well as determining the mechanism of Ikaros function in cytokine gene expression. We are also interested in determining if Ikaros regulates regulatory T cell development and function.

3) A novel role for Ikaros in microRNA expression

MicroRNAs (miRNAs) are endogenous, single-stranded RNA molecules that regulate gene expression at the post-transcriptional level. They are known to play a role in most biological processes including regulation of T cell differentiation and function. Interestingly, most miRNAs have multiple targets, such that one miRNA could have profound effects on the program of gene expression in a cell. Currently, very little is known about transcriptional regulators involved in activation and repression of miRNA expression. Since Ikaros is involved in a vast array of processes in blood cell development and function, and the mechanisms by which it does this are still largely unknown, we hypothesize that Ikaros could influence expression of a large number of genes through a role in regulation of specific miRNAs. Using miRNA array analyses, we have identified miRNAs that are differentially expressed in Ikaros null and wild type CD4 T cells. One of these has been linked to regulation of a signaling pathway downstream of T cell receptor (TCR) stimulation, the PI3-kinase pathway. This is particularly interesting since, in the absence of Ikaros, T cells are hyper-responsive to TCR signals. We plan to further investigate this potential mechanism underlying the hyperproliferative phenotype of Ikaros null T cells and to characterize Ikaros’ role in regulation of this, and other, miRNAs in T cells.

 Publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Winandy S. Ikaros to the rescue of TCR-a chain gene rearrangement. Eur J Immunol. 2013 Feb; 43(2):314-7. PMID: 23299235.
    View in: PubMed
  2. Malinge S, Thiollier C, Chlon TM, Doré LC, Diebold L, Bluteau O, Mabialah V, Vainchenker W, Dessen P, Winandy S, Mercher T, Crispino JD. Ikaros inhibits megakaryopoiesis through functional interaction with GATA-1 and NOTCH signaling. Blood. 2013 Mar 28; 121(13):2440-51. PMID: 23335373.
    View in: PubMed
  3. Toubai T, Sun Y, Tawara I, Friedman A, Liu C, Evers R, Nieves E, Malter C, Chockley P, Maillard I, Winandy S, Reddy P. Ikaros-Notch axis in host hematopoietic cells regulates experimental graft-versus-host disease. Blood. 2011 Jul 7; 118(1):192-204. PMID: 21471527.
    View in: PubMed
  4. Chari S, Umetsu SE, Winandy S. Notch target gene deregulation and maintenance of the leukemogenic phenotype do not require RBP-J kappa in Ikaros null mice. J Immunol. 2010 Jul 1; 185(1):410-7. PMID: 20511547.
    View in: PubMed
  5. Umetsu SE, Winandy S. Ikaros is a regulator of Il10 expression in CD4+ T cells. J Immunol. 2009 Nov 1; 183(9):5518-25. PMID: 19828627.
    View in: PubMed
  6. Urban JA, Brugmann W, Winandy S. Cutting Edge: Ikaros null thymocytes mature into the CD4 lineage with reduced TCR signal: A study using CD3{zeta} immunoreceptor tyrosine-based activation motif transgenic mice. J Immunol. 2009 Apr 1; 182(7):3955-9. PMID: 19299690.
    View in: PubMed
  7. Quirion MR, Gregory GD, Umetsu SE, Winandy S, Brown MA. Cutting edge: Ikaros is a regulator of Th2 cell differentiation. J Immunol. 2009 Jan 15; 182(2):741-5. PMID: 19124715.
    View in: PubMed
  8. Chari S, Winandy S. Ikaros regulates Notch target gene expression in developing thymocytes. J Immunol. 2008 Nov 1; 181(9):6265-74. PMID: 18941217.
    View in: PubMed
  9. Reynaud D, Demarco IA, Reddy KL, Schjerven H, Bertolino E, Chen Z, Smale ST, Winandy S, Singh H. Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros. Nat Immunol. 2008 Aug; 9(8):927-36. PMID: 18568028.
    View in: PubMed
  10. Kathrein KL, Chari S, Winandy S. Ikaros directly represses the notch target gene Hes1 in a leukemia T cell line: implications for CD4 regulation. J Biol Chem. 2008 Apr 18; 283(16):10476-84. PMID: 18287091.
    View in: PubMed
  11. Thomas RM, Chunder N, Chen C, Umetsu SE, Winandy S, Wells AD. Ikaros enforces the costimulatory requirement for IL2 gene expression and is required for anergy induction in CD4+ T lymphocytes. J Immunol. 2007 Dec 1; 179(11):7305-15. PMID: 18025173.
    View in: PubMed
  12. Winandy S, Brown M. No DL1 Notch ligand? GATA be a mast cell. Nat Immunol. 2007 Aug; 8(8):796-8. PMID: 17641659.
    View in: PubMed
  13. Wojcik H, Griffiths E, Staggs S, Hagman J, Winandy S. Expression of a non-DNA-binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis. Eur J Immunol. 2007 Apr; 37(4):1022-32. PMID: 17357110.
    View in: PubMed
  14. Gregory GD, Raju SS, Winandy S, Brown MA. Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE. J Clin Invest. 2006 May; 116(5):1327-36. PMID: 16628252.
    View in: PubMed
  15. Winandy S. Regulation of chromatin structure during thymic T cell development. J Cell Biochem. 2005 Jun 1; 95(3):466-77. PMID: 15832342.
    View in: PubMed
  16. Kathrein KL, Lorenz R, Innes AM, Griffiths E, Winandy S. Ikaros induces quiescence and T-cell differentiation in a leukemia cell line. Mol Cell Biol. 2005 Mar; 25(5):1645-54. PMID: 15713624.
    View in: PubMed
  17. Urban JA, Winandy S. Ikaros null mice display defects in T cell selection and CD4 versus CD8 lineage decisions. J Immunol. 2004 Oct 1; 173(7):4470-8. PMID: 15383578.
    View in: PubMed
  18. Winandy S, Wu L, Wang JH, Georgopoulos K. Pre-T cell receptor (TCR) and TCR-controlled checkpoints in T cell differentiation are set by Ikaros. J Exp Med. 1999 Oct 18; 190(8):1039-48. PMID: 10523602.
    View in: PubMed
  19. Kim J, Sif S, Jones B, Jackson A, Koipally J, Heller E, Winandy S, Viel A, Sawyer A, Ikeda T, Kingston R, Georgopoulos K. Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity. 1999 Mar; 10(3):345-55. PMID: 10204490.
    View in: PubMed
  20. Avitahl N, Winandy S, Friedrich C, Jones B, Ge Y, Georgopoulos K. Ikaros sets thresholds for T cell activation and regulates chromosome propagation. Immunity. 1999 Mar; 10(3):333-43. PMID: 10204489.
    View in: PubMed
  21. Koipally J, Kim J, Jones B, Jackson A, Avitahl N, Winandy S, Trevisan M, Nichogiannopoulou A, Kelley C, Georgopoulos K. Ikaros chromatin remodeling complexes in the control of differentiation of the hemo-lymphoid system. Cold Spring Harb Symp Quant Biol. 1999; 64:79-86. PMID: 11232340.
    View in: PubMed
  22. Georgopoulos K, Winandy S, Avitahl N. The role of the Ikaros gene in lymphocyte development and homeostasis. Annu Rev Immunol. 1997; 15:155-76. PMID: 9143685.
    View in: PubMed
  23. Winandy S, Wu P, Georgopoulos K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell. 1995 Oct 20; 83(2):289-99. PMID: 7585946.
    View in: PubMed
  24. Georgopoulos K, Bigby M, Wang JH, Molnar A, Wu P, Winandy S, Sharpe A. The Ikaros gene is required for the development of all lymphoid lineages. Cell. 1994 Oct 7; 79(1):143-56. PMID: 7923373.
    View in: PubMed
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