BIOMEDICAL SCIENCES GRADUATE PROGRAM SUMMER 2013

Transcription

1 THE OHIO STATE UNIVERSITY BIOMEDICAL SCIENCES GRADUATE PROGRAM SUMMER 2013 Edward Lloyd Briercheck PhD Candidate Elucidation of the Mechanism by which Phosphatase and Tensin Homologue Deleted on Chromosome Ten (PTEN) Regulates Natural Killer Cell Function June 17, 2013 Meiling Hall Room :00 AM

2 VITA July, Born Uniontown, PA May Jackson High School May B.S. University of Toledo May 2006-Present..... M.S.T.P Program The Ohio State University College of Medicine COMMITTEE MEMBERS Professor Michael A. Caligiuri, M.D. (Advisor) Professor William E. Carson, III, M.D. Professor Gregory B. Lesinski, Ph.D. Professor Guido Marcucci, M.D.

3 ABSTRACT Human natural killer (NK) cells are CD56 + CD3 - large granular lymphocytes of the innate immune system which are characterized by the ability to both directly kill and initiate an immune response to virally infected or malignantly transformed cells. Human NK cells in peripheral blood can be divided into two developmentally and functionally distinct subsets based upon surface expression of CD56. In contrast to the more mature CD56 dim NK cell, the less mature CD56 bright NK cell is unable to kill malignant cells at rest. We sought to determine the mechanism of this difference in cytolytic activity by exploring changes in gene expression between CD56 bright NK cells and CD56 dim NK cells. We observed that CD56 bright NK cells showed a ~5 fold increase in PTEN protein expression over CD56 dim NK cells. Human and murine NK cells overexpressing PTEN demonstrated decreased cytolytic activity and IFN-γ secretion, with concurrent decreases in their downstream (MAPK and AKT) targets that are critical for cytolysis. Paradoxically, human NK cells with near complete PTEN knockdown also showed decreased cytolytic activity despite elevations in AKT and MAPK. Confocal microscopy revealed that near complete PTEN knockdown results in a disruption of the NK cell s ability to organize immunological synapse components including decreased adhesion, decreased polarization of the microtubule organizing center toward the target cell and a decrease in coalescence of cytolytic granules. Thus, PTEN is differentially expressed in mature human NK cell subsets and our studies suggest it must be expressed at an optimum level to maximize NK cytolytic activity.

4 RECENT ABSTRACTS AND PRESENTATION [This must be the first line on Page 8] Briercheck EL., Trotta R., Cole JP., Cole TC., Hartlage AH., Banerjee PP., Hsu HT., Mao C., Chen L., Ciralariello PD., Pandolfi PP., Martin C., Leone G., Orange, JS., Caligiuri MA. (2013). Phosphatase and tensin homologue deleted on chromosome ten (PTEN): A critical balance of expression is required for maximum natural killer cell cytolysis of tumor cells. International Conference on Innate Immunity, Kos, Greece. Briercheck EL., Trotta R., Cole J., Cole T., Hartlage A., Martin C., Leone G., Caligiuri MA. (2012). Human natural killer (NK) cells: differential expression of phosphatase and tensin homologue deleted on chromosome ten (PTEN) during NK cell development regulates its cytolytic activity against leukemic target cells, in 54th ASH Annual Meeting and Exposition Atlanta, GA. Briercheck EL The Ohio State University College of Medicine Research Day, Alan Yates Speaker Series. Columbus, OH, The role of PTEN in human natural Killer cells: Implications for Cowden Syndrome.. Briercheck EL, Trotta R, Ciarlarello D, Caligiuri MA.The American Physician Scientists Association Annual meeting. Chicago IL, The role of PTEN in human natural Killer cells: Implications for Cowden Syndrome. Briercheck EL., University of Salford-University of Toledo Exchange 25 th Anniversary Symposium, Toledo OH, Natural Killer Cells: Controlling infection and Curing Cancer.. Briercheck EL, Trotta, R., Yu J, Ciarlariello D, Caligiuri MA The Ohio State University College of Medicine Research Day, Columbus, OH Subsets of peripheral blood natural killer cells differentially express the 3 phosphatase, phosphatase and tensin homolog (PTEN).. Biomedical Sciences Graduate Program 1170 Graves Hall 333 W. 10 th Avenue Columbus, Ohio 43210

5 AWARDS AND HONORS The Ohio State University Wexner Medical Center MD/PhD Travel Award for Outstanding Poster (2013) American Society of Hematology Trainee Travel Award. Pelotonia Graduate Research Fellowship (2011). American Society of Clinical Investigation (ASCI) Annual Meeting travel award (2011) MD/PhD Leadership Award, The Ohio State University College of Medicine, 2007 The Ohio State University, University Graduate Fellowship, 2007 FUTURE PLANS I will be returning to the clinic for my last two years of medical school and then pursuing residency training. I look forward to a career of caring for patients, while working on the development new therapeutic strategies.

6 RECENT PUBLICATIONS Trotta R, Chen L, Costinean S, Josyula S, Mundy-Bosse BL, Ciarlariello D, Mao C, Briercheck EL, McConnell KK, Mishra A, Yu L, Croce CM, Caligiuri MA. Blood Feb 19 Overexpression of mir-155 cause expansion, arrest in terminal differentiation and functional activation of mouse natural killer cells. Blood Feb 19 [Epub ahead of print] Chang JS, Santhanam R, Trotta R, Neviani P, Eiring AM, Briercheck E, Rochetti M, Roy DC, Calabretta B, Caligiuri MA. High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBPalpha-driven myeloid differentiation. Blood 110(2): , McClory S, Hughes T, Freud AG, Briercheck EL, Martin C, Trimboli AJ, Yu J, Zhang X, Leone G, Nuovo G, Caligiuri MA. Evidence for a stepwise program of extrathymic T cell development within the human tonsil. J Clin Invest Apr 2;122(4): Trotta R, Ciarlariello D, Dal Col J, Mao H, Chen L, Briercheck EL, Yu J, Zhang J, Perrotti D, Caligiuri MA. The PP2A inhibitor SET regulates granzyme B expression in human natural killer cells. Blood Feb 24;117(8): doi: /blood Epub 2010 Dec 14. Hughes T, Becknell B, McClory S, Briercheck EL, Yu J, Mao C, Giovenzana C, Nuovo G, Wei L, Zhang X, Gavrilin M, Wewers M, Caligiuri MA. IL-1β selectively expands and sustains IL-22(+) immature natural killer cells in secondary lymphoid tissue. Immunity Jun 25;32(6): Briercheck EL, Freud A, Caligiuri MA. Natural Killer Cells: Basic Science and Clinical Application Nov 2009 Human Natural Killer cell development, Elsevier. Hughes T, Becknell B, McClory S, Briercheck EL, Freud AG, Zhang X, Mao C, Nuovo GJ, Yu J, Caligiuri MA. Stage 3 immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the Th17 cytokine interleukin-22. Blood 113(17): , 2009.