Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancy

López-Nevado, MartaPaz Artal, Estela NatividadAllende Martínez, Luis Miguel2025-01-142025-01-142022-09-06López-Nevado M, Ortiz-Martín J, Serrano C, Pérez-Saez MA, López-Lorenzo JL, Gil-Etayo FJ, Rodríguez-Frías E, Cabrera-Marante O, Morales-Pérez P, Rodríguez-Pinilla MS, Manso R, Salgado-Sánchez RN, Cerdá-Montagud A, Quesada-Espinosa JF, Gómez-Rodríguez MJ, Paz-Artal E, Muñoz-Calleja C, Arranz-Sáez R, Allende LM. Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancy. J Clin Immunol. 2023 Jan;43(1):165-180. doi: 10.1007/s10875-022-01361-y. Epub 2022 Sep 6. PMID: 36066697.0271-91421573-259210.1007/s10875-022-01361-yhttps://hdl.handle.net/20.500.14352/114123malignancies. More recently, biallelic, and monoallelic germline mutations conferring susceptibility to lymphoid and myeloid cancer have been described. We report two unrelated autoimmune lymphoproliferative syndrome-like patients who presented with T-cell lymphoma associated with novel germline biallelic or monoallelic mutations in the TET2 gene. Both patients presented a history of chronic lymphoproliferation with lymphadenopathies and splenomegaly, cytopenias, and immune dysregulation. We identified the first compound heterozygous patient for TET2 mutations (P1) and the first ALPS-like patient with a monoallelic TET2 mutation (P2). P1 had the most severe form of autosomal recessive disease due to TET2 loss of function resulting in absent TET2 expression and profound increase in DNA methylation. Additionally, the immunophenotype showed some alterations in innate and adaptive immune system as inverted myeloid/plasmacytoid dendritic cells ratio, elevated terminally differentiated effector memory CD8 + T-cells re-expressing CD45RA, regulatory T-cells, and Th2 circulating follicular T-cells. Double-negative T-cells, vitamin B12, and IL-10 were elevated according to the ALPS-like suspicion. Interestingly, the healthy P1’s brother carried a TET2 mutation and presented some markers of immune dysregulation. P2 showed elevated vitamin B12, hypergammaglobulinemia, and decreased HDL levels. Therefore, novel molecular defects in TET2 confirm and expand both clinical and immunological phenotype, contributing to a better knowledge of the bridge between cancer and immunity.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancyjournal articlehttps://doi.org/10.1007/s10875-022-01361-yopen access611.4Síndrome linfoproliferativo autoinmuneDiagnóstico Síndrome linfoproliferativo autoinmune* / genéticaProteínas de unión al ADN / genéticaMutación de la línea germinalCiencias Biomédicas32 Ciencias Médicas