title: Dasatinib therapy results in decreased B cell proliferation, splenomegaly, and tumor growth in a murine model of lymphoma expressing Myc and Epstein-Barr virus LMP2A.
abstract: Epstein-Barr virus (EBV) infection and latency has been associated with malignant diseases including nasopharyngeal carcinoma, Hodgkin lymphoma, Burkitt lymphoma, and immune deficiency associated lymphoproliferative diseases. EBV-encoded latent membrane protein 2A (LMP2A) recruits Lyn and Syk kinases via its SH2-domain binding motifs, and modifies their signaling pathways. LMP2A transgenic mice develop hyperproliferative bone marrow B cells and immature peripheral B cells through modulation of Lyn kinase signaling. LMP2A/λ-MYC double transgenic mice develop splenomegaly and cervical lymphomas starting at 8 weeks of age. We reasoned that targeting Lyn in LMP2A-expressing B cells with dasatinib would provide a therapeutic option for EBV-associated malignancies. Here, we show that dasatinib inhibits B cell colony formation by LMP2A transgenic bone marrow cells, and reverses splenomegaly and tumor growth in both a pre-tumor and a syngeneic tumor transfer model of EBV-associated Burkitt lymphoma. Our data support the idea that dasatinib may prove to be an effective therapeutic molecule for the treatment of EBV-associated malignancies.
authors.affiliation: Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Ward 6-245, Chicago, IL, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Dargart
authors.forename: Kamonwan
authors.initials: K
authors.lastname: Fish
authors.forename: Leo I
authors.initials: LI
authors.lastname: Gordon
authors.forename: Richard
authors.initials: R
authors.lastname: Longnecker
authors.forename: Osman
authors.initials: O
authors.lastname: Cen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001402:B-Lymphocytes / Q000187:drug effects*; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D000069439:Dasatinib; D004195:Disease Models, Animal; D015870:Gene Expression; D004854:Herpesvirus 4, Human / Q000472:pathogenicity; D051379:Mice; D008822:Mice, Transgenic; D016274:Oncogene Protein p55(v-myc) / Q000096:biosynthesis*; D011743:Pyrimidines / Q000008:administration & dosage*; D013163:Splenomegaly / Q000188:drug therapy / Q000473:pathology; D013844:Thiazoles / Q000008:administration & dosage*; D014763:Viral Matrix Proteins / Q000096:biosynthesis*
chemical_list: D000970:Antineoplastic Agents; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016274:Oncogene Protein p55(v-myc); D011743:Pyrimidines; D013844:Thiazoles; D014763:Viral Matrix Proteins; D000069439:Dasatinib