Project Grant R01AI182056

REMODELING OF THE HOST EPIGENOME DURING EBV INFECTION - PROJECT SUMMARY IN EBV+ LYMPHOMAS VIRAL PROTEIN EXPRESSION IS THE ONCOGENIC DRIVER AND PROGRESSIVE FORCE. HOWEVER, THE MECHANISMS BY WHICH EBV INFECTION ALTERS B CELL BIOLOGY TO CONTRIBUTE TO THE DEVELOPMENT OF EBV+ LYMPHOMAS ARE NOT WELL UNDERSTOOD. EBV INFECTION OF PRIMARY B LYMPHOCYTES RESULTS IN CELL ACTIVATION, PROLIFERATION, AND IMMORTALIZATION. THESE PROGRAMS ARE INDUCED BY EBV MIMICKING THE NORMAL ACTIVATION OF B CELLS BY ANTIGENS OR T CELLS. SINCE LMP1 IS NEEDED FOR EBV TO TRANSFORM NAIVE B CELLS INTO IMMORTALIZED B CELLS, CONSIDERABLE WORK HAS BEEN ATTEMPTED TO PHARMACOLOGICALLY TARGET THE LMP1-ACTIVATED ONCOGENIC PATHWAYS. HOWEVER, IN VIVO ATTEMPTS TO TARGET THESE PATHWAYS HAVE FAILED TO ABOLISH EBV-DRIVEN ONCOGENESIS COMPLETELY. THIS LACK OF EFFICACY OF THE TARGETED APPROACHES SUGGESTED TO US THAT ANOTHER, UNDISCOVERED OR UNAPPRECIATED, ONCOGENIC MECHANISM DOWNSTREAM OF LMP1 MIGHT BE AT WORK. THIS PROPOSAL AIMS TO IDENTIFY THE MECHANISM BY WHICH EBV INFECTION CONTRIBUTES TO DEVELOPING B CELL MALIGNANCIES. OUR RECENT, PUBLISHED WORK SHOWED THAT THE EBV ONCOPROTEIN LMP1 ACTIVATES THE CHROMATIN-ASSOCIATED FACTOR PARP1 TO EPIGENETICALLY REGULATE GENES THAT ARE IMPORTANT FOR SUSTAINING CELL PROLIFERATION. EXPANDING UPON THESE FINDINGS, OUR PRELIMINARY DATA INDICATE THAT THE REORGANIZATION OF THE 3D STRUCTURE AND FUNCTION OF CHROMATIN IN B CELLS IS A NOVEL AND UNDERAPPRECIATED MECHANISM TARGETED BY EBV THROUGH LMP1 TO ALTER GENE EXPRESSION AND REPROGRAMMING IN EBV INFECTED CELLS. WE DISCOVERED THAT: 1) EXPRESSION OF LMP1 ALONE IS SUFFICIENT TO ALTER THE 3D STRUCTURE OF THE B CELL GENOME; 2) THE EBV/LMP1-INDUCED CHANGES IN CHROMATIN STRUCTURE ARE ASSOCIATED WITH PARP1 ACTIVITY, AND WITH OCCUPANCY BY THE CHROMATIN ORGANIZERS CTCF AND YY1; 3) EBV ACTIVATION OF PARP1 REQUIRES ERK ACTIVATION BY LMP1; AND 4) PARP INHIBITORS ELICIT CYTOTOXICITY IN EBV+ LYMPHOMAS IN VIVO. BASED ON THESE PRELIMINARY DATA AND OUR PREVIOUS WORK WE HYPOTHESIZE THAT IN EBV+ B CELLS, LMP1 EXPRESSION ACTIVATES, VIA THE ERK PATHWAY, PARP1, PROMOTING CONFORMATIONAL CHANGES IN THE HOST GENOME ARCHITECTURE THAT DRIVE ONCOGENESIS. WE WILL ALSO TEST THE HYPOTHESIS THAT PARP1 IS AN ATTRACTIVE THERAPEUTIC TARGET FOR EBV LYMPHOMAS.