Targeting TET2 as a Therapeutic Approach for Angioimmunoblastic T Cell Lymphoma

SIMPLE SUMMARY: Recent advances in exome sequencing and comprehensive genomic studies have shed new light on the pathogenesis and mutational landscape of Angioimmunoblastic T-cell lymphoma (AITL). The essential pathogenic role of recurrent TET2, DNMT3A, IDH2, and RHOA mutations in AITL has been identified. Notably, the detection of TET2 mutations in bystander B cells in AITL samples has allowed new mechanistic advances in AITL combined with B-cell lymphoma. In this review, we highlight the current role of TET2 mutations in the pathogenesis of AITL and how mutational crosstalk in TET2 and other partner genes (RHOA, DNMT3A, and IDH2) cooperate to contribute to the disease. In addition, we elaborate on recent advances in AITL frequently comprising B-cell lymphoma and discuss the potential prospects of targeting TET2 as an anti-AITL agent. ABSTRACT: Angioimmunoblastic T-cell lymphoma (AITL), a type of malignant lymphoma with unique genomic aberrations, significant clinicopathological features, and poor prognosis, is characterized by immune system dysregulation. Recent sequencing studies have identified recurrent mutations and interactions in tet methylcytosine dioxygenase 2 (TET2), ras homology family member A (RHOA), DNA methyltransferase 3 alpha (DNMT3A), and mitochondrial isocitrate dehydrogenase II (IDH2). Notably, since B-cell lymphomas are frequently observed along with AITL, this review first summarizes its controversial mechanisms based on traditional and recent views. Epigenetic regulation represented by TET2 plays an increasingly important role in understanding the multi-step and multi-lineage tumorigenesis of AITL, providing new research directions and treatment strategies for patients with AITL. Here, we review the latest advances in our understanding of AITL and highlight relevant issues that have yet to be addressed in clinical practice.