My research work focuses on the epigenetic regulator Enhancer of Zeste Homolog 2 (EZH2) and associated intracellular signaling molecules in the tumorigenesis of hematopoietic malignancies. EZH2 is the enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2), an important epigenetic regulator. It functions as a methyltransferase, targeting lysine 27 on histone H3 and leading to its trimethylation (H3K27me3). Our previous studies of a range of low- and high-grade B-cell lymphomas showed that EZH2 expression correlates with aggressive disease behavior, suggesting that this molecule functions as an oncogenic protein in these neoplasms. There is evidence for the regulation of EZH2 by different signaling cascades in various aggressive B-cell lymphomas: p-ERK-related signaling in diffuse large B-cell lymphoma and MYC-related signaling in Burkitt lymphoma and double-hit lymphoma. In a series of separate studies focusing on histiocytic and dendritic cell neoplasms, as well as Hodgkin lymphomas and related large B-cell lymphomas, we revealed different mechanisms of EZH2 and associated signaling cascades that contribute to tumorigenesis in these malignancies. All these works have provided a deeper understanding of the role of EZH2 and related signaling molecules in these lymphoid neoplasms, which could lead to potential therapeutic strategies targeting this molecule (see the proposed model below). As an example, one of the EZH2 inhibitors, Tazemetostat (TAZVERIK, Epizyme, Inc.), has recently been approved by the FDA for the treatment of refractory follicular lymphoma.
We aim to further investigate the mechanisms of EZH2 and associated intracellular signaling molecules in their contributions to tumorigenesis. We are also focused on establishing prognostic criteria for a spectrum of hematopoietic and non-hematopoietic malignancies. Our studies include examining various intracellular signaling molecules that regulate EZH2 expression in different types of mature T-cell neoplasms; investigating the mutation status of the EZH2 gene at the molecular level and its effects on disease aggressiveness or prognostic value; and deepening our understanding of EZH2's role in myeloid neoplasms, such as acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms, and its relationship to other co-existing molecular abnormalities. Additionally, we are exploring the role of the oncogenic signaling cascade, specifically JAK2/STAT activation, in upregulating programmed death ligand 1 (PD-L1) expression and facilitating PD-L1-mediated immune escape in myeloid neoplasms. This research aims to elucidate the regulation of EZH2 and its potential association with PD-1/PD-L1 expression, ultimately enhancing our understanding of how to tailor potential therapies targeting EZH2-related molecules and PD-L1-mediated immunotherapy for specific molecular mutation subgroups within myeloid neoplasms.