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Br J Haematol. 2016 Apr;173(2):265-73. doi: 10.1111/bjh.13952. Epub 2016 Feb 25.

Genes encoding members of the JAK-STAT pathway or epigenetic regulators are recurrently mutated in T-cell prolymphocytic leukaemia.

Author information

1
Institute for Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig Holstein, Kiel, Germany.
2
Department of Paediatrics, Christian-Albrechts-University Kiel & University Hospital Schleswig Holstein, Kiel, Germany.
3
Cell Networks, Bioquant, University of Heidelberg, Heidelberg, Germany.
4
Department of Haematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
5
Faculty of Medicine, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.
6
Second Department of Medicine, University Hospital of Schleswig-Holstein, Kiel, Germany.
7
Department of Haematology, Hospital Clínic, Institut d'Investigaciones Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.
8
Haematopathology Unit, Hospital Clínic, Institut d'Investigaciones Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
9
Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK.
10
German Cancer Consortium (DKTK), Heidelberg, Germany.

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.

KEYWORDS:

JAK3; STAT5B; T-cell lymphoma; T-cell prolymphocytic leukaemia; epigenetic regulators

PMID:
26917488
DOI:
10.1111/bjh.13952
[Indexed for MEDLINE]

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