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The Zhang Lab’s research proceeds along two directions.

Using genetically modified mice, we study the molecular pathogenesis of human diffuse large B cell lymphoma (DLBCL) and EBV-associated B cell lymphoma

We use B cell lymphoma mouse models to reveal the surveillance mechanism of the immune system on tumor formation and develop strategies to harness immune cells for tumor therapy

Genetically engineered mice are crucial for our research, as they allow us to assess the causal role of the mutation event and the cooperation of multiple such events in lymphomagenesis, as well as to follow up disease dynamics in vivo. Mouse models also allow us to reveal the role of the immune system in tumor control.

DLBCL, the most common type of B cell lymphoma, is a genetically and clinically heterogeneous disease. Gene expression profile studies revealed several subtypes, including germinal center B cell (GCB)-like and activated B cell (ABC)-like DLBCL. The less curable ABC-DLBCL often carries genetic lesions leading to constitutive NF-κB activation and interference with terminal B cell differentiation; the latter lesions include deletion/mutation of BLIMP1 and translocation of BCL6. Using conditional gain- and/or loss-of-function mutagenesis in mice, we have demonstrated the cooperation of the canonical NF-κB signaling and disruption of BLIMP1 in the pathogenesis of ABC-DLBCL. Mechanistically, we showed that the canonical NF-κB signaling enhances B cell proliferation and survival, while the loss of BLIMP1 abrogates B cell terminal differentiation, a non-proliferating state. Furthermore, our recent data reveal the synergy of the alternative (non-canonical) NF-κB signaling with deregulation of BCL6 in DLBCL pathogenesis.

EBV is a γ-Herpes virus that 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. Therefore, EBV is associated with post-transplant lymphoproliferative disorder (PTLD) and AIDS-related lymphoma in patients whose immune system is impaired. We have generated mice expressing the EBV latent membrane protein 1 (LMP1) specifically in B cells and found that, like human EBV-infected cells, LMP1+ B cells are cleared by T cells; breaking immune surveillance results in rapid generation of B cell lymphomas, which resemble EBV-driven lymphomas in immunosuppressed patients. These findings revealed a central role of LMP1 in both lymphomagenesis and the induction of immune surveillance. In this work, we also found that CD4+ T cells are superior to CD8+ T cells in the control of LMP1+ B cells/lymphoma cells.

We are now using these mouse models to discover recurrent secondary hits, whose cooperative role with the primary oncogenic events (the gain- and/or loss-of-function alleles engineered in the mice) is suggested by the clonal nature of the lymphomas. The identified mutations will be validated in the corresponding human tumors, and their molecular feature and oncogenic mechanism will be further studied in gene-modified mice.

We are also engaged in projects to uncover the mechanism of how CD4+ T cells control lymphomas, and reveal their possible regulation by other types of immune cells, using model systems already established in the lab.