JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL
by
Linus Wahnschaffe 1,2,3,†, Till Braun 1,2,3,†
, Sanna Timonen 4,5,6,†, Anil K. Giri 6, Alexandra Schrader 1,2,3, Prerana Wagle 2, Henrikki Almusa 6, Patricia Johansson 7, Dorine Bellanger 8,9, Cristina López 10,11, Claudia Haferlach 12, Marc-Henri Stern 8,9, Jan Dürig 7,13, Reiner Siebert 10,11, Satu Mustjoki 4,5, Tero Aittokallio 6,14 and Marco Herling 1,2,3,*
Linus Wahnschaffe 1,2,3,†, Till Braun 1,2,3,†, Sanna Timonen 4,5,6,†, Anil K. Giri 6, Alexandra Schrader 1,2,3, Prerana Wagle 2, Henrikki Almusa 6, Patricia Johansson 7, Dorine Bellanger 8,9, Cristina López 10,11, Claudia Haferlach 12, Marc-Henri Stern 8,9, Jan Dürig 7,13, Reiner Siebert 10,11, Satu Mustjoki 4,5, Tero Aittokallio 6,14 and Marco Herling 1,2,3,*
1
Department I of Internal Medicine, Center for Integrated Oncology (CIO), Aachen-Bonn-Cologne-Duesseldorf, University of Cologne (UoC), 50937 Cologne, Germany
2
Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, 50937 Cologne, Germany
3
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany
4
Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, FI-00029 Helsinki, Finland
5
Translational Immunology Research program and Department of Clinical Chemistry and Hematology, University of Helsinki, FI-00014 Helsinki, Finland
6
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014 Helsinki, Finland
7
Department of Hematology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
8
Institut Curie, Centre de Recherche, 75248 Paris, France
9
French National Institute of Health and Medical Research (INSERM) U830, 75248 Paris, France
10
Institute for Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig Holstein, 24105 Kiel, Germany
11
Institute of Human Genetics, Ulm University, Ulm University Medical Center, D-89081 Ulm, Germany
12
MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, 81377 Munich, Germany
13
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
14
Department of Mathematics and Statistics, University of Turku, FI-20014 Turku, Finland
*
Author to whom correspondence should be addressed.
†
Equal contribution.
Cancers 2019, 11(12), 1833; https://doi.org/10.3390/cancers11121833
Received: 17 October 2019 / Revised: 14 November 2019 / Accepted: 18 November 2019 / Published: 21 November 2019
(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)
T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell leukemia. Recent studies detected genomic aberrations affecting JAK and STAT genes in T-PLL. Due to the limited number of primary patient samples available, genomic analyses of the JAK/STAT pathway have been performed in rather small cohorts. Therefore, we conducted—via a primary-data based pipeline—a meta-analysis that re-evaluated the genomic landscape of T-PLL. It included all available data sets with sequence information on JAK or STAT gene loci in 275 T-PLL. We eliminated overlapping cases and determined a cumulative rate of 62.1% of cases with mutated JAK or STAT genes. Most frequently, JAK1 (6.3%), JAK3 (36.4%), and STAT5B (18.8%) carried somatic single-nucleotide variants (SNVs), with missense mutations in the SH2 or pseudokinase domains as most prevalent. Importantly, these lesions were predominantly subclonal. We did not detect any strong association between mutations of a JAK or STAT gene with clinical characteristics. Irrespective of the presence of gain-of-function (GOF) SNVs, basal phosphorylation of STAT5B was elevated in all analyzed T-PLL. Fittingly, a significant proportion of genes encoding for potential negative regulators of STAT5B showed genomic losses (in 71.4% of T-PLL in total, in 68.4% of T-PLL without any JAK or STAT mutations). They included DUSP4, CD45, TCPTP, SHP1, SOCS1, SOCS3, and HDAC9. Overall, considering such losses of negative regulators and the GOF mutations in JAK and STAT genes, a total of 89.8% of T-PLL revealed a genomic aberration potentially explaining enhanced STAT5B activity. In essence, we present a comprehensive meta-analysis on the highly prevalent genomic lesions that affect genes encoding JAK/STAT signaling components. This provides an overview of possible modes of activation of this pathway in a large cohort of T-PLL. In light of new advances in JAK/STAT inhibitor development, we also outline translational contexts for harnessing active JAK/STAT signaling, which has emerged as a ‘secondary’ hallmark of T-PLL.
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Keywords:
JAK; STAT; T-PLL; T-cell leukemia; meta-analysis; STAT5B signaling
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MDPI and ACS Style
Wahnschaffe, L.; Braun, T.; Timonen, S.; Giri, A.K.; Schrader, A.; Wagle, P.; Almusa, H.; Johansson, P.; Bellanger, D.; López, C.; Haferlach, C.; Stern, M.-H.; Dürig, J.; Siebert, R.; Mustjoki, S.; Aittokallio, T.; Herling, M. JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL. Cancers 2019, 11, 1833.
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