Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
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
_version_ 1783488775663386624
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
work_keys_str_mv AT wahnschaffelinus jakstatactivatinggenomicalterationsareahallmarkoftpll
AT brauntill jakstatactivatinggenomicalterationsareahallmarkoftpll
AT timonensanna jakstatactivatinggenomicalterationsareahallmarkoftpll
AT girianilk jakstatactivatinggenomicalterationsareahallmarkoftpll
AT schraderalexandra jakstatactivatinggenomicalterationsareahallmarkoftpll
AT wagleprerana jakstatactivatinggenomicalterationsareahallmarkoftpll
AT almusahenrikki jakstatactivatinggenomicalterationsareahallmarkoftpll
AT johanssonpatricia jakstatactivatinggenomicalterationsareahallmarkoftpll
AT bellangerdorine jakstatactivatinggenomicalterationsareahallmarkoftpll
AT lopezcristina jakstatactivatinggenomicalterationsareahallmarkoftpll
AT haferlachclaudia jakstatactivatinggenomicalterationsareahallmarkoftpll
AT sternmarchenri jakstatactivatinggenomicalterationsareahallmarkoftpll
AT durigjan jakstatactivatinggenomicalterationsareahallmarkoftpll
AT siebertreiner jakstatactivatinggenomicalterationsareahallmarkoftpll
AT mustjokisatu jakstatactivatinggenomicalterationsareahallmarkoftpll
AT aittokalliotero jakstatactivatinggenomicalterationsareahallmarkoftpll
AT herlingmarco jakstatactivatinggenomicalterationsareahallmarkoftpll