P1271: ELUCIDATING TUMOR SUPPRESSOR FUNCTIONS OF TET2 IN B CELL LYMPHOMAS

Abstract

Background: Remodeling of the epigenetic landscape via DNA cytosine methylation directs cell lineage specification, establishing and maintaining gene expression programs that uniquely define given cell types. During tumorigenesis the epigenome becomes corrupted, impairing lineage-specific gene expression programs. TET2, an enzyme that contributes to the erasure of cytosine methylation via oxidation of the 5’ methyl group, is among the most frequent somatically mutated genes in human hematological tumors, commonly identified as loss-of-function versions. In mouse models, TET2 loss on its own is only weakly tumorigenic, but rather facilitates leukemic transformation driven by prototypic oncogenes such as AML-ETO or FLT3ITD. However, TET2 LOF is not limited to leukemias. In B cell malignancies, TET2 is found mutated in a fraction of diffuse large B cell lymphomas (DLBCL), which display a distinct gene expression profile. Aims: Having established a role for TET2 loss-of-function in enhancing MYC-driven lymphomas, our overall aim is to understand how TET2 loss conspires with MYC to overcome the barriers that maintain cell identity and function. Methods: Using pre-clinical mouse models and in vitro culture systems, we establish that TET2 loss boosts the formation of B cell lymphomas driven by the MYC oncoprotein. Results: Thus, (1) TET2 deficiency specifically in B cells facilitates MYC-mediated transformation in a dose dependent manner, and (2) TET2 deficiency early on in hematopoietic stem and progenitor cells enhances the transformative potential later on in antigen-activated B cells. Our data suggest that TET2 may exert tumor suppressor functions via controlling the expression of DNA repair genes, or via direct functions of oxidized cytosine species. In addition, TET2-deficient lymphomas select for high expression of the pro-survival BCL2 family protein BCLXL, potentially providing protection from MYC-driven apoptosis. Summary/Conclusion: Altogether, our data concerning the impact of TET2 loss-of-function on DNA repair and apoptosis mechanisms creates understanding of how TET2 deficiency nudges transformation, and reveals testable therapeutic vulnerabilities.