Abstract 5379: TET2 loss and the lymphoma-associated RHOA mutation cooperate to disrupt CD4+ T cell function

Abstract

Abstract Peripheral T cell lymphomas (PTCLs) are a group of rare but aggressive lymphomas derived from mature T cells or natural killer cells with a dismal prognosis. Current treatments for PTCL are ineffective with high relapse rates, largely owing to the lack of targeted therapeutics and a deep mechanistic understanding of the molecular etiology. Recent exome sequencing has unveiled the frequent co-existing somatic mutations in RHOA (G17V) and TET2 in PTCLs, but not in other types of hematological malignancies. Most notably, mutations in both TET2 and RHOA are frequently observed (~60-70%) in angioimmunoblastic T-cell lymphoma (AITL), which is among the most common subtypes of PTCLs with a median overall survival of approximately 1.5 years. Patients with AITL are often associated with autoimmune manifestations, but the mechanistic underpinnings remain unresolved. To examine whether TET2 loss and RhoAG17V alter mature T cell function, we performed adoptive T cell transfer experiments with WT or Tet2 knockout transgenic mice. Using this strategy, we generated four groups of recipient mice transferred with T cells as follows: WT, RhoAG17V, Tet2-/-, or Tet2-/-RhoAG17V. Among these four groups, only recipient mice transferred with double mutant T cells displayed severe inflammatory-like phenotypes that ultimately led to early lethality in mice. Moribund mice transferred with Tet2-/-RhoAG17V T cells showed substantial weight loss, severe skin ulcer on tail/paw/ear accompanied with pruritus, and lymphomegaly as typically seen in AITL patients. Histopathological analysis on major organs derived from the Tet2-/-RhoAG17V group indicated severe infiltration of both T and B lymphocytes in major organs, as well as a pronounced increase in the numbers of follicles and activated germinal centers in lymph nodes. Further analysis indicates that Tet2 loss and RhoAG17V mutation cooperated together to exclusively promote CD4+ T cell proliferation and survival, and exert no adverse effects on CD8+ T cells, which recapitulates the mutation spectrum detected in AITL patients, i.e., RhoAG17V is primarily detected in CD4+ T cells but not other T cell subsets. The functional consequence of Tet2 loss and RhoAG17V expression in CD4+ T cells is characterized by an imbalance between the effector and regulatory T cells, which may account for the overt immunoinflammatory phenotypes seen in mouse models. The transcriptome analysis further revealed a pronounced remodeling of the immune signaling network that points to the aberrant expression of several key transcriptional factors. In summary, our study demonstrated a previously-unappreciated cooperativity between Tet2 loss and RhoAG17V mutation in disrupting mature CD4+ T cells function, which is made through the synergy between epigenetic and GTPase signaling pathways. The results obtained from this study provide an additional basis for future development of new diagnosis, prognosis and therapy for PTCL patients. Note: This abstract was not presented at the meeting. Citation Format: Shengbing Zang, Jia Li, Haiyan Yang, Wei Han, Jixiang Zhang, Minjung Lee, Yubin Zhou, Deqiang Sun, Yun Huang. TET2 loss and the lymphoma-associated RHOA mutation cooperate to disrupt CD4+ T cell function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5379. doi:10.1158/1538-7445.AM2017-5379