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JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL
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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966610/ https://www.ncbi.nlm.nih.gov/pubmed/31766351 http://dx.doi.org/10.3390/cancers11121833 |
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author | Wahnschaffe, Linus Braun, Till Timonen, Sanna Giri, Anil K. Schrader, Alexandra Wagle, Prerana Almusa, Henrikki Johansson, Patricia Bellanger, Dorine López, Cristina Haferlach, Claudia Stern, Marc-Henri Dürig, Jan Siebert, Reiner Mustjoki, Satu Aittokallio, Tero Herling, Marco |
author_facet | Wahnschaffe, Linus Braun, Till Timonen, Sanna Giri, Anil K. Schrader, Alexandra Wagle, Prerana Almusa, Henrikki Johansson, Patricia Bellanger, Dorine López, Cristina Haferlach, Claudia Stern, Marc-Henri Dürig, Jan Siebert, Reiner Mustjoki, Satu Aittokallio, Tero Herling, Marco |
author_sort | Wahnschaffe, Linus |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6966610 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69666102020-02-04 JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL Wahnschaffe, Linus Braun, Till Timonen, Sanna Giri, Anil K. Schrader, Alexandra Wagle, Prerana Almusa, Henrikki Johansson, Patricia Bellanger, Dorine López, Cristina Haferlach, Claudia Stern, Marc-Henri Dürig, Jan Siebert, Reiner Mustjoki, Satu Aittokallio, Tero Herling, Marco Cancers (Basel) Article 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. MDPI 2019-11-21 /pmc/articles/PMC6966610/ /pubmed/31766351 http://dx.doi.org/10.3390/cancers11121833 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Wahnschaffe, Linus Braun, Till Timonen, Sanna Giri, Anil K. Schrader, Alexandra Wagle, Prerana Almusa, Henrikki Johansson, Patricia Bellanger, Dorine López, Cristina Haferlach, Claudia Stern, Marc-Henri Dürig, Jan Siebert, Reiner Mustjoki, Satu Aittokallio, Tero Herling, Marco JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL |
title | JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL |
title_full | JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL |
title_fullStr | JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL |
title_full_unstemmed | JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL |
title_short | JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL |
title_sort | jak/stat-activating genomic alterations are a hallmark of t-pll |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966610/ https://www.ncbi.nlm.nih.gov/pubmed/31766351 http://dx.doi.org/10.3390/cancers11121833 |
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