Germline TET2 loss of function causes childhood immunodeficiency and lymphoma
| Autor: | Sinisa Savic, James A. Poulter, Andrew J. Cant, Eamonn Sheridan, Helen Griffin, Dylan Lawless, Sophie Hambleton, Neil V. Morgan, Stefan Przyborski, Siti Mardhiana Mohamad, Rashida Anwar, Jennifer Shrimpton, Clive Carter, Gina M. Doody, Karin R. Engelhardt, Kevin Windebank, Meghan Acres, Catherine Cargo, Stephan Ehl, Frédéric Rieux-Laucat, Chris M. Bacon, Sean O’Riordan, Anne Rensing-Ehl, Jarmila Stremenova Spegarova, Majlinda Lako, Philip Chetcuti, Aneta Mikulasova |
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| Rok vydání: | 2020 |
| Předmět: |
Male
medicine.medical_treatment T cell Induced Pluripotent Stem Cells Immunology B-Lymphocyte Subsets Mutation Missense Apoptosis Hematopoietic stem cell transplantation Biology medicine.disease_cause Biochemistry Germline Dioxygenases Neoplasms Multiple Primary Fatal Outcome Immune system Germline mutation Loss of Function Mutation T-Lymphocyte Subsets Proto-Oncogene Proteins Exome Sequencing medicine Humans Cellular Reprogramming Techniques Germ-Line Mutation Immunodeficiency Hematopoietic Stem Cell Transplantation Infant Newborn Lymphoma T-Cell Peripheral Cell Biology Hematology DNA Methylation Immune dysregulation Allografts medicine.disease Lymphoproliferative Disorders Pedigree DNA-Binding Proteins medicine.anatomical_structure Codon Nonsense Autoimmune lymphoproliferative syndrome Cancer research Female Severe Combined Immunodeficiency Lymphoma Large B-Cell Diffuse |
| Zdroj: | Blood. 136:1055-1066 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.2020005844 |
| Popis: | Molecular 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. |
| Databáze: | OpenAIRE |
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