Ana Miletic Sedy
Postdoctoral Fellow

amiletic@sanfordburnham.org

PTEN/SHIP signaling pathways in normal and neoplastic B cells

Despite successes in the development and application of B cell-specific therapeutics for B cell lymphomas, several type of lymphoma remain untreatable.  We have found that germline deletion of the inositol phosphatases PTEN and SHIP in the B lineage cells (bPTEN/SHIP^-/-) leads to a lethal lymphoma that with 100% penetrance, indicating that SHIP, as well as PTEN, is a tumor suppressor.  This model system represents a novel system in which to elucidate the molecular mechanisms of B-Non-Hodgkin’s lymphoma (B-NHL) progression and metastasis.  Specifically, I am investigating 1) the relevance of the B lymphoma observed in bPTEN/SHIP^-/- mice to human B cell lymphoma, 2) the mitogenic and/or survival signals that are required for lymphoma development and progression, and 3) the differences between lymphoid versus metastatic B lymphoma cells. Ultimately, we would like to use what is discovered for the rational design of next-generation therapeutics for the treatment of B lymphomas.

Ana is the recipient of a  Ruth L. Kirschstein National Research Service Award Fellowship.

Education
2000-2006 Washington University School of Medicine, Saint Louis, Missouri, Ph.D. in Immunology, May 2006                                      

1996-1999 Knox College, Galesburg, Illinois, B.A. in Biochemistry, (cumlaude), June 1999

Publications

R.C. Rickert, J. Jellusova and A.V. Miletic. 2011. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol. Rev. 244(1):115-33. doi: 10.1111/j.1600-065X.2011.01067.x.

Baracho G.V., Miletic A.V., Omori S.A., Cato M.H., Rickert R.C. Emergence of the PI3-kinase pathway as a central modulator of normal and aberrant B cell differentiation. 2011. Curr Opin Immunol. Apr;23(2):178-83.

Miletic A.V., A.N. Anzelon-Mills, D.M. Mills, S.A. Omori, I.M. Pedersen, D-M Shin, J.V. Ravetch, S. Bolland, H. C. Morse III and R.C. Rickert. 2010. Coordinate Suppression of B Cell Lymphoma by PTEN and SHIP Phosphatases. J. Exp. Med. 207(11):2407-20.

Miletic A.V.*, Graham D.B.*, Sakata-Sogawa K.*, Hiroshima M., Hamann M.J., Cemerski S., Kloeppel T., Billadeau D.D., Kanagawa O., Tokunaga M., Swat W. Vav Links the T Cell Antigen Receptor to the Actin Cytoskeleton and T Cell Activation Independently of Intrinsic Guanine Nucleotide Exchange Activity. PLoS One. 2009 4(8):e6599.

Wu S., Vossius S., Rahmouni S., Miletic A.V., Vang T., Vazquez-Rodriguez J., Cerignoli F., Arimura F., Williams S., Hayes T., Moutschen M., Vasile S., Pellecchia M., Mustelin T., Tautz L. Multidentate Small-Molecule Inhibitors of Vaccinia H1-related (VHR) Phosphatase Decrease Proliferation of Cervix Cancer Cells. 2009. J. Med. Chemistry. Nov 12;52(21):6716-23.

Liu J.Y., Seno H., Miletic A.V., Mills J.C., Swat W., Stappenbeck T.S. Vav proteins are necessary for correct differentiation of mouse cecal and colonic enterocytes. 2009. J Cell Sci. 2009 Feb 1;122(Pt 3):324-34.

Pedersen, I.M., D. Otero, E. Kao, A.V Miletic, C. Hother, E. Ralfkiaer, R.C. Rickert, K. Gronbaek and Michael David.  2009. Onco-miR-155 targets SHIP1 to promote TNFa-dependent growth of B cell lymphomas. EMBO Mol. Med 2009.

Vang, T., A.V. Miletic, Y. Arimura, L. Tautz, R.C. Rickert and T. Mustelin. Protein Tyrosine Phosphatases in Autoimmunity. Ann. Rev. of Immunol. 2007 Oct 11; doi:10.1146/annurev.immunol.26.021607.090418.

Stephenson L.M., Sammut B., Graham D.B., Chan-Wang J., Brim K.L., Huett A.S., Miletic A.V., Kloeppel T., Landry A., Xavier R., Swat W. DLGH1 Is a Negative Regulator of T-Lymphocyte Proliferation. Mol Cell Biol. 2007 Nov;27(21):7574-81.

Vang T., Miletic A.V., Bottini N., Mustelin T. Protein tyrosine phosphatase PTPN22 in human autoimmunity. Autoimmunity. 2007 Sep;40(6):453-61.

Miletic A.V.*, Graham D.B.*, Vivianne Montgrain, Fujikawa K., Kloeppel T., Brim K., Weaver B.K., Schreiber R.D., Xavier R., Swat W. Vav proteins control MyD88-dependent oxidative burst. Blood. 2007 Apr 15;109(8):3360-8.

Miletic A.V., Sakata-Sogawa K., Hiroshima M., Hamann M.J., Gomez T.S., Ota N., Kloeppel T., Kanagawa O., Tokunaga M,. Billadeau D.D., Swat W. 2006. VAV1 acidic region tyrosine 174 is required for the formation of TCR-induced microclusters and is essential in T cell development and activation. 2006. J of Biol Chem. Dec 15;281(50):38257-65.

Stephenson L.M., Miletic A.V., Kloeppel T., Kusin S., Swat W. Vav proteins regulate the plasma cell program and secretory immunoglobin production. 2006. J Immunol. 177(4):2349-55.

Charvet C., Canonigo A.J., Becart S., Maurer U., Miletic A.V., Swat W., Deckert M., Altman A. Vav1 promotes T cell cycle progression by linking TCR/CD28 costimulation to FOXO1 and p27kip1 expression. 2006. J Immunol. 177(8):5024-31.

Graham, D.B., Cella M., Giurisato E., Fujikawa K., Miletic A.V., Kloeppel T., Brim K., Takai T., Shaw A.S., Colonna M., Swat W. Vav1 controls DAP10-mediated NK cell natural cytotoxicity. 2006. J Immunol. 177(4):2349-55.

Fujikawa K.,* Miletic A.V.,* Alt F.W., Faccio T., Brown T., Hoog J., Fredericks J., Nishi S., Mildiner S.L., Brugge J., Rosen F.S., Swat W. Vav 1/2/3-null mice define an essential role for Vav family proteins in lymphocyte development and activation but a differential requirement in MAPK signaling in T and B cells. 2003. J Exp Med. 198 (10): 1595-1608.

Miletic A.V., Swat M., Fujikawa K., Swat W. Cytoskeletal remodeling in lymphocyte activation. 2003. Curr Opin Immunol. 15(3): 261-268.

Kanagawa O, Miletic A.V., Vaupel B. Regulation of diabetes development by regulatory T cells in pancreatic islet antigen-specific TCR transgenic nonobese diabetic mice. 2002. J Immunol. 168(12): 6159-64.

* denotes equal authorship

Outside Interests
Include gardening and plants, playing soccer, and hiking and traveling with my husband John.