Our research effort proceeds along two directions. First, we use genetically modified mice to study the molecular pathogenesis of B cell lymphomas, particularly the diffuse large B cell lymphoma (DLBCL). Second, we focus on understanding a new immune surveillance mechanism on Epstein-Barr virus (EBV) infection and the associated B cell malignancies.
DLBCL is the most common lymphoid malignancy. The integration of gene expression and various sequencing technologies has dramatically accelerated our phenotypic and genetic understanding of the disease. Various DLBCL subtypes and their featured genetic lesions have been revealed. To understand the functional significance and operating mechanisms of these lesions, we recapitulate these genetic events, individually or in combination, in mice. As a consequence, these studies may identify attractive targets for therapeutic intervention.
EBV specifically infects, and can transform, human B cells. More than 90% of the human population is EBV-infected. The infected B cells are rapidly cleared by the immune system, but B cells harboring “dormant” virus persist at low frequency for life. Under conditions of immunosuppression, the virus can be reactivated and spread from these few cells, resulting in rapid expansion of infected B cells and their malignant transformation, as seen in pathologies such as post-transplant lymphoproliferative disorder (PTLD) and AIDS-related lymphoma. Our recent work in a transgenic mouse model revealed a new immune surveillance mechanism against EBV-infected B cells that is induced by the oncoprotein latent membrane protein 1 (LMP1). We are currently focusing on understanding how LMP1 induces immune surveillance, and how to leverage such understanding to develop effective immunotherapy strategies.
Zhang B, Calado DP, Wang Z, Frohler S, Kochert K, Qian Y, Koralov S, Schmidt-Supprian M, Sasaki Y, Unitt C, Rodig S, Chen W, Dalla-Favera R, Alt FW, Pasqualucci L, Rajewsky K. An Oncogenic Role for Alternative NF-B Signaling in DLBCL Revealed upon Deregulated BCL6 Expression. Cell Reports. 2015, 11(5): 715-26.
Sander S, Calado, DP, Srinivasan L, Kochert K, Zhang B, Rosolowski M, Rodig S, Holzmann K, Stilgenbauer S, Siebert R, Bullinger L, Rajewsky K. Synergy between PI3K Signalling and MYC in Burkitt Lymphomagenesis. Cancer Cell. 2012, 22(2): 167-79.
Zhang B, Kracker S, Yasuda T, Casola S, Vanneman M, Hömig-Hölzel C, Wang Z, Derudder E, Li S, Chakraborty T, Cotter SE, Koyama S, Currie T, Freeman GJ, Kutok JL, Rodig SJ, Dranoff G, Rajewsky K. Immune Surveillance and Therapy of Lymphomas Driven by Epstein-Barr-Virus Protein LMP1 in a Mouse Model. Cell. 2012, 148(4): 739-51.
Calado DP, Zhang B, Srinivasan L, Sasaki Y, Seagal J, Unitt C, Rodig S, Kutok J, Tarakhovsky A, Schmidt-Supprian M, Rajewsky K. Constitutive canonical NF-B activation cooperates with disruption of Blimp1 in the pathogenesis of activated B cell-like diffuse large cell lymphoma. Cancer Cell. 2010, 18(6): 580-9.
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