Jarmila Spegarova, United Kingdom
Newcastle University Institute of Cellular MedicinePresenter of 1 Presentation
GERMLINE TET2 LOSS-OF-FUNCTION CAUSES CHILDHOOD IMMUNODEFICIENCY WITH LYMPHOMA PREDISPOSITION
Abstract
Background and Aims
The molecular dissection of inborn errors of immunity can help to elucidate non-redundant functions of key genes and pathways. We investigated three patients from two unrelated consanguineous families diagnosed with an autosomal recessive syndrome of combined immunodeficiency, manifesting as lymphadenopathy, hepatosplenomegaly, susceptibility to infections, and lymphoma in childhood.
Methods
Immunologic investigations included flow cytometric immunophenotyping, lymphocyte proliferation and apoptosis assays. Whole exome sequencing (WES) data were interrogated for rare, homozygous, predicted deleterious variants, and their pathogenicity was explored. Relevant assays of protein expression and enzymatic function were performed. Total blood DNA methylation and in vitro differentiation potential of patient-derived B-cells and induced pluripotent stem cells (iPSC)-derived haematopoietic cells were studied.
Results
WES revealed homozygous missense and nonsense mutations within Tet methylcytosine dioxygenase 2 (TET2), a known epigenetic regulator of gene expression; its somatic loss-of-function mutations are associated with myeloid and lymphoid malignancies. Mutated TET2 protein was either absent or enzymatically defective for 5-hydroxymethylating activity in vitro. DNA methylation in total blood was reduced. Both patients with the p.H1382R mutation and clinically significant autoimmunity showed defective lymphocyte apoptosis, consistent with autoimmune lymphoproliferative syndrome. Moreover, patient’s B-cells were unable to generate plasma cells and produce IgG. The haematopoietic potential of patients-derived iPSC was skewed towards the myeloid lineage. Patients’ lymphoma tissue revealed acquisition of somatic mutations in genes within the RAS signalling pathway.
Conclusions
In this study, we defined the molecular and clinical consequences of germline TET2 impairment in immunodeficient patients, leading to altered DNA methylation, B-cell maturation, skewed haematopoiesis, and development of lymphomas.
***J. Spegarova, D. Lawless, S. Savic, and S. Hambleton have contributed equally to this work.