Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases

• Published in: Leukemia Vol. 26; no. 5; pp. 963 - 971
• Main Authors: Linka, R M, Risse, S L, Bienemann, K, Werner, M, Linka, Y, Krux, F, Synaeve, C, Deenen, R, Ginzel, S, Dvorsky, R, Gombert, M, Halenius, A, Hartig, R, Helminen, M, Fischer, A, Stepensky, P, Vettenranta, K, Köhrer, K, Ahmadian, M R, Laws, H-J, Fleckenstein, B, Jumaa, H, Latour, S, Schraven, B, Borkhardt, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2012; Nature Publishing Group
• Subjects: 631/208/737; 692/699/249/1623; 692/699/67/1858; Binding Sites; Biological and medical sciences; Bruton's tyrosine kinase; Cancer Research; Child; Child, Preschool; Critical Care Medicine; Epstein-Barr virus; Female; Gene mutations; Genetic aspects; Germ-Line Mutation; Health aspects; Hematologic and hematopoietic diseases; Hematology; Herpesvirus 4, Human - physiology; Homology; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunology; Immunopathology; Immunoproliferative diseases; Infectious diseases; Intensive; Interleukin 2; Internal Medicine; Itk protein; Kinases; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoproliferative disorders; Lymphoproliferative Disorders - virology; Male; Medical sciences; Medicine; Medicine & Public Health; Mutants; Mutation; Mutation, Missense; Oncology; original-article; Patients; Pediatrics; Pedigree; Phosphatidylinositol; Phosphatidylinositol 3,4,5-triphosphate; Phosphatidylinositol 4,5-diphosphate; Phosphorylation; Physiological aspects; Pleckstrin; Protein kinases; Protein-tyrosine kinase; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proteins; Risk factors; SH2D1A protein; Tyrosine; Viral diseases; Virology; XIAP protein; Germany; France; Paris France; primary immunodeficiency; EBV; ITK; kinase; loss-of-function; lymphoma; Epstein Barr virus; Interleukin 2; Lymphoproliferative syndrome; Primary; Genetics; Gammaherpesvirinae; Human; Immunopathology; Hematology; Enzyme; Herpesviridae; Transferases; Cytokine; Malignant hemopathy; Lymphoid neoplasm; Immune deficiency; Lymphoma; Infection; Virus; Kinase; Viral disease; Mutation; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2011.371

The purpose of this study was the appraisal of the clinical and functional consequences of germline mutations within the gene for the IL-2 inducible T-cell kinase, ITK. Among patients with Epstein-Barr virus-driven lymphoproliferative disorders (EBV-LPD), negative for mutations in SH2D1A and XIAP ( n =46), we identified two patients with R29H or D500T,F501L,M503X mutations, respectively. Human wild-type (wt) ITK, but none of the mutants, was able to rescue defective calcium flux in murine Itk −/− T cells. Pulse-chase experiments showed that ITK mutations lead to varying reductions of protein half-life from 25 to 69% as compared with wt ITK (107 min). The pleckstrin homology domain of wt ITK binds most prominently to phosphatidylinositol monophosphates (PI(3)P, PI(4)P, PI(5)P) and to lesser extend to its double or triple phosphorylated derivates (PIP2, PIP3), interactions which were dramatically reduced in the patient with the ITK R29H mutant. ITK mutations are distributed over the entire protein and include missense, nonsense and indel mutations, reminiscent of the situation in its sister kinase in B cells, Bruton's tyrosine kinase.