Germline TET2 loss of function causes childhood immunodeficiency and lymphoma

• DOI: 10.1182/blood.2020005844
• Publication Date: 2020-06-10T02:16:00Z
• Authors: Jarmila Stremenov...; Dylan Lawless; Siti Mardhiana Bi...; Karin R. Engelhardt; Gina Doody; Jennifer Shrimpton; Anne Rensing-Ehl; Stephan Ehl; Frederic Rieux-La...; Catherine Cargo; Helen Griffin; Aneta Mikulasova; Meghan Acres; Neil V. Morgan; James A. Poulter; Eamonn G. Sheridan; Philip Chetcuti; Sean O'Riordan; Rashida Anwar; Clive R. Carter; Stefan Przyborski; Kevin Windebank; Andrew J. Cant; Majlinda Lako; Chris M. Bacon; Sinisa Savic; Sophie Hambleton
• Keywords: Male; 0303 health sciences; Induced Pluripotent Stem Cells; B-Lymphocyte Subsets; Hematopoietic Stem Cell Transplantation; Infant, Newborn; 610; Lymphoma, T-Cell, Peripheral; Apoptosis; DNA Methylation; Allografts; Lymphoproliferative Disorders; Dioxygenases; 3. Good health; DNA-Binding Proteins; 03 medical and health sciences; Fatal Outcome; Codon, Nonsense; Loss of Function Mutation; Humans; Cellular Reprogramming Techniques; Female; Lymphoma, Large B-Cell, Diffuse; Germ-Line Mutation

AbstractMolecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.