S105 EXABS-214-TCL New Insights Into the Pathogenesis of T-Cell Lymphoma and How This May Guide Treatment Laurence de Leval, MD, PhD1,*, and Bettina Bisig, MD, PhD1 1University Hospital and Lausanne University, Institute of Pathology, Department of Laboratory Medicine and Pathology, rue du Bugnon 25, 1011 Lausanne, Switzerland *Corresponding author: Laurence.deleval@chuv.ch Keywords T-cell lymphoma, mutations, epigenetics, pathogenesis, targeted therapy Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of malignancies (>30 entities) derived from mature T or natural killer (NK) cells, representing less than 10% of all non-Hodgkin lymphomas. They may present as predominantly leukemic, or as primarily nodal, extranodal or cutaneous diseases. With few exceptions, PTCLs are usually aggressive. Advances in molecular and genomic profiling of PTCLs have contributed to refining diagnostic and classification criteria, and to a better understanding of their pathogenesis, resulting in significant changes and conceptual shifts in the two recent (2022) classifications of lymphoid neoplasms, namely the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO5). In PTCL, mutations and copy number variations frequently target different classes of epigenetic modifiers, T-cell receptor and coreceptors signaling pathways, and components or regulators of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Although a few variants are characteristic of certain entities, there is overlap in the mutational landscapes of different diseases. Immune evasion has also emerged as another oncogenic mechanism in PTCLs. CD274/PD-L1 is expressed in some neoplasms, suggesting that PD-1 blockade may represent an efficient therapy in some patients; however, because PD-1 also acts as a tumor suppressor which is inactivated in a fraction of PTCLs, PD-1 checkpoint inhibition may also potentially lead to unwanted effects. Constitutive genetic background may confer susceptibility to PTCL development, as suggested by HLA associations to celiac disease and enteropathy-associated T-cell lymphoma (EATL), and also demonstrated by the recent finding of germline HAVCR2 mutations altering TIM-3 in subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome. Lymph node involvement represents the most common clinical presentation of PTCLs, corresponding to three main groups of diseases: systemic anaplastic large cell lymphomas (ALCLs), positive or negative for anaplastic lymphoma kinase (ALK), follicular helper T-cell lymphoma (TFHL) and PTCL, not otherwise specified (NOS). ALK+ ALCL, defined by the presence of ALK fusions encoding oncogenic proteins, typically identified by immunohistochemistry. ALK tyrosine kinase inhibitors have efficacy in some clinical settings. NOTCH pathway activation, resulting from recurrent NOTCH1 mutations or ALK fusions, represent another candidate therapeutic target. Among ALKnegative ALCLs, DUSP22-rearranged cases have distinctive biological features. ALK+ ALCL and about two-thirds of ALK- ALCL share STAT3-mediated oncogenesis; genetic alterations driving STAT3 activation in ALK- ALCL include JAK1 and STAT3 mutations, and rearrangements involving ROS1, TYK2, FRK and JAK2. Therapies targeting the JAK/STAT pathway are being explored. TP53 mutations are detected in a small subset of cases, associated with worse outcome. The notion of cell-of-origin as an important determinant of nodal PTCL classification is best exemplified by follicular helper T-cell lymphoma (TFHL), considered as one disease or a group of related entities. TFHLs, which frequently carry mutations of TET2, DNMT3A, RHOA and IDH2, rarely seen in combination in other PTCL, have a higher response rate to hypomethylating agents such as 5-azacytidine and histone deacetylase inhibitors such as romidepsin. The background clonal hematopoiesis appears to be the source of myeloid neoplasms seen in TFHL patients, particularly after cytotoxic therapy. Data are accumulating to support that a similar cell-of-origin concept might be relevant to characterize meaningful subgroups of PTCL, NOS, namely TBX21- and GATA-3- PTCL, NOS, based on cytotoxic and/ or Th1 versus Th2 signatures. PTCL-GATA3 demonstrates high genomic complexity characterized by biallelic deletion/mutation of TP53, CDKN2A/B, or RB1, and carries a worse prognosis compared to PTCL-TBX21 which shows low genomic complexity and few recurrent specific genetic changes. Extranodal PTCL entities derive mostly from innate cells, are relatively organ-specific, and often portend poor outcome. Frequent oncogenic activation of the JAK/STAT pathway may be an attractive therapeutic target. Among primary intestinal entities,
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