title: Genes encoding members of the JAK-STAT pathway or epigenetic regulators are recurrently mutated in T-cell prolymphocytic leukaemia.
abstract: T-cell prolymphocytic leukaemia (T-PLL) is an aggressive leukaemia. The primary genetic alteration in T-PLL are the inv(14)(q11q32)/t(14;14)(q11;q32) leading to TRD/TRA-TCL1A fusion, or the t(X;14)(q28;q11) associated with TRD/TRA-MTCP1 fusion. However, additional cooperating abnormalities are necessary for emergence of the full neoplastic phenotype. Though the pattern of secondary chromosomal aberrations is remarkably conserved, targets of the changes are largely unknown. We analysed a cohort of 43 well-characterized T-PLL for hotspot mutations in the genes JAK3, STAT5B and RHOA. Additionally, we selected a subset of 23 T-PLL cases for mutational screening of 54 genes known to be recurrently mutated in T-cell and other haematological neoplasms. Activating mutations in the investigated regions of the JAK3 and STAT5B genes were detected in 30% (13/43) and 21% (8/39) of the cases, respectively, and were mutually exclusive. Further, we identified mutations in the genes encoding the epigenetic regulators EZH2 in 13% (3/23), TET2 in 17% (4/23) and BCOR in 9% (2/23) of the cases. We confirmed that the JAK-STAT pathway is a major mutational target, and identified epigenetic regulators recurrently mutated in T-PLL. These findings complement the mutational spectrum of secondary aberrations in T-PLL and underscore the potential therapeutical relevance of epigenetic regulators in T-PLL.
authors.affiliation: Institute for Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig Holstein, Kiel, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: López
authors.affiliation: Institute for Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig Holstein, Kiel, Germany.|Department of Paediatrics, Christian-Albrechts-University Kiel & University Hospital Schleswig Holstein, Kiel, Germany.
authors.forename: Anke K
authors.initials: AK
authors.lastname: Bergmann
authors.affiliation: Institute for Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig Holstein, Kiel, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Paul
authors.affiliation: Institute for Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig Holstein, Kiel, Germany.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Murga Penas
authors.affiliation: Institute for Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig Holstein, Kiel, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Nagel
authors.affiliation: Cell Networks, Bioquant, University of Heidelberg, Heidelberg, Germany.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Betts
authors.affiliation: Department of Haematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.|Faculty of Medicine, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Johansson
authors.affiliation: Second Department of Medicine, University Hospital of Schleswig-Holstein, Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ritgen
authors.affiliation: Department of Haematology, Hospital Clínic, Institut d'Investigaciones Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Tycho
authors.initials: T
authors.lastname: Baumann
authors.affiliation: Haematopathology Unit, Hospital Clínic, Institut d'Investigaciones Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Aymerich
authors.affiliation: Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Jayne
authors.affiliation: Cell Networks, Bioquant, University of Heidelberg, Heidelberg, Germany.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Russell
authors.affiliation: Haematopathology Unit, Hospital Clínic, Institut d'Investigaciones Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.affiliation: Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK.
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.affiliation: Department of Haematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Dürig
authors.affiliation: Institute for Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig Holstein, Kiel, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D053616:Janus Kinase 3 / Q000235:genetics*; D015461:Leukemia, Prolymphocytic, T-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012008:Recurrence; D012097:Repressor Proteins / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000235:genetics
chemical_list: C411984:BCOR protein, human; D014408:Biomarkers, Tumor; D005819:Genetic Markers; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D020742:rhoA GTP-Binding Protein
keywords: JAK3; STAT5B; T-cell lymphoma; T-cell prolymphocytic leukaemia; epigenetic regulators