Identifying Epigenetic Vulnerabilities in Peripheral T-Cell Lymphomas

Angioimmunoblastic T-cell lymphomas (AITL) are some of the most aggressive blood cancers. These tumors are highly resistant to current chemotherapy treatments, resulting in cure rates of less than 30%. Importantly, analyses of patient samples have identified new specific genetic alterations characteristic of these high-risk lymphomas, including: (i) loss of function in the Tet2 gene, which is responsible of regulating when and where genes are activated via the writing and erasing of so called DNA epigenetic marks, and (ii) a very frequent mutation, Rhoa G17V, that controls the differentiation of T-cells. Combining these mutations, we have now generated the first mouse model of AITL. This accurate animal model recapitulates all features of the human disease and that can be used to understand the mechanisms that drive lymphoma development and as therapeutic platform to rapidly test new drugs and drug combinations. Classic approaches for the treatment of T-cell lymphoma have yielded little progress, thus identification, testing and optimization of new highly active targeted drugs is a priority in the field. Epigenetic drugs constitute a group of therapeutics that have shown some promising results in AITL. However, only a fraction of patients responds, and those who show clinical improvement have typically only transient responses followed by tumor progression and still ultimately die of their disease. Moreover the mechanism of action of these drugs remains incompletely understood, which limits our capacity to develop improved rationally designed therapies. Thus, there is an unmet need to improve our understanding on the mechanisms that mediate the antitumor activity of epigenetic therapies and to develop more effective drugs and drug combinations. We propose that mutations in epigenetic factors together with Rhoa G17V fundamentally change DNA epigenetic marks that govern normal T cell development and promote AITL. Here we will undertake an in-depth analysis of DNA epigenetic marks to define the impact of Tet2 and Rhoa G17V in lymphoma development and to investigate how these genetic alterations influence the response to epigenetic therapies in the clinic. Fundamental conceptual innovation in this project results from our identification of a cooperative effect of loss of function mutations in epigenetic regulators and Rhoa G17V to induce lymphoma, while technical innovation is driven by newly developed genetically manipulated mouse model and state-of-the-art experimental approaches, including the in-depth analyses of epigenetic marks and characterization of gene function at the single cell level. The potential impact of this research resides on the understanding of the disease biology in T-cell lymphoma and improve the identification of patients that would benefit the most from treatment with epigenetic drugs, leading to better outcomes.