Cargando…

Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation

T-cell large granular lymphocytic (T-LGL) leukemia is a clonal disease characterized by the expansion of mature CD3+CD8+ cytotoxic T cells. It is often associated with autoimmune disorders and immune-mediated cytopenias. Our recent findings suggest that up to 40% of T-LGL patients harbor mutations i...

Descripción completa

Detalles Bibliográficos
Autores principales: Andersson, E I, Rajala, H L M, Eldfors, S, Ellonen, P, Olson, T, Jerez, A, Clemente, M J, Kallioniemi, O, Porkka, K, Heckman, C, Loughran, T P, Maciejewski, J P, Mustjoki, S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877422/
https://www.ncbi.nlm.nih.gov/pubmed/24317090
http://dx.doi.org/10.1038/bcj.2013.65
_version_ 1782297644265111552
author Andersson, E I
Rajala, H L M
Eldfors, S
Ellonen, P
Olson, T
Jerez, A
Clemente, M J
Kallioniemi, O
Porkka, K
Heckman, C
Loughran, T P
Maciejewski, J P
Mustjoki, S
author_facet Andersson, E I
Rajala, H L M
Eldfors, S
Ellonen, P
Olson, T
Jerez, A
Clemente, M J
Kallioniemi, O
Porkka, K
Heckman, C
Loughran, T P
Maciejewski, J P
Mustjoki, S
author_sort Andersson, E I
collection PubMed
description T-cell large granular lymphocytic (T-LGL) leukemia is a clonal disease characterized by the expansion of mature CD3+CD8+ cytotoxic T cells. It is often associated with autoimmune disorders and immune-mediated cytopenias. Our recent findings suggest that up to 40% of T-LGL patients harbor mutations in the STAT3 gene, whereas STAT5 mutations are present in 2% of patients. In order to identify putative disease-causing genetic alterations in the remaining T-LGL patients, we performed exome sequencing from three STAT mutation-negative patients and validated the findings in 113 large granular lymphocytic (LGL) leukemia patients. On average, 11 CD8+ LGL leukemia cell-specific high-confidence nonsynonymous somatic mutations were discovered in each patient. Interestingly, all patients had at least one mutation that affects either directly the STAT3-pathway (such as PTPRT) or T-cell activation (BCL11B, SLIT2 and NRP1). In all three patients, the STAT3 pathway was activated when studied by RNA expression or pSTAT3 analysis. Screening of the remaining 113 LGL leukemia patients did not reveal additional patients with same mutations. These novel mutations are potentially biologically relevant and represent rare genetic triggers for T-LGL leukemia, and are associated with similar disease phenotype as observed in patients with mutations in the STAT3 gene.
format Online
Article
Text
id pubmed-3877422
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-38774222014-01-02 Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation Andersson, E I Rajala, H L M Eldfors, S Ellonen, P Olson, T Jerez, A Clemente, M J Kallioniemi, O Porkka, K Heckman, C Loughran, T P Maciejewski, J P Mustjoki, S Blood Cancer J Original Article T-cell large granular lymphocytic (T-LGL) leukemia is a clonal disease characterized by the expansion of mature CD3+CD8+ cytotoxic T cells. It is often associated with autoimmune disorders and immune-mediated cytopenias. Our recent findings suggest that up to 40% of T-LGL patients harbor mutations in the STAT3 gene, whereas STAT5 mutations are present in 2% of patients. In order to identify putative disease-causing genetic alterations in the remaining T-LGL patients, we performed exome sequencing from three STAT mutation-negative patients and validated the findings in 113 large granular lymphocytic (LGL) leukemia patients. On average, 11 CD8+ LGL leukemia cell-specific high-confidence nonsynonymous somatic mutations were discovered in each patient. Interestingly, all patients had at least one mutation that affects either directly the STAT3-pathway (such as PTPRT) or T-cell activation (BCL11B, SLIT2 and NRP1). In all three patients, the STAT3 pathway was activated when studied by RNA expression or pSTAT3 analysis. Screening of the remaining 113 LGL leukemia patients did not reveal additional patients with same mutations. These novel mutations are potentially biologically relevant and represent rare genetic triggers for T-LGL leukemia, and are associated with similar disease phenotype as observed in patients with mutations in the STAT3 gene. Nature Publishing Group 2013-12 2013-12-06 /pmc/articles/PMC3877422/ /pubmed/24317090 http://dx.doi.org/10.1038/bcj.2013.65 Text en Copyright © 2013 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Andersson, E I
Rajala, H L M
Eldfors, S
Ellonen, P
Olson, T
Jerez, A
Clemente, M J
Kallioniemi, O
Porkka, K
Heckman, C
Loughran, T P
Maciejewski, J P
Mustjoki, S
Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation
title Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation
title_full Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation
title_fullStr Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation
title_full_unstemmed Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation
title_short Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation
title_sort novel somatic mutations in large granular lymphocytic leukemia affecting the stat-pathway and t-cell activation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877422/
https://www.ncbi.nlm.nih.gov/pubmed/24317090
http://dx.doi.org/10.1038/bcj.2013.65
work_keys_str_mv AT anderssonei novelsomaticmutationsinlargegranularlymphocyticleukemiaaffectingthestatpathwayandtcellactivation
AT rajalahlm novelsomaticmutationsinlargegranularlymphocyticleukemiaaffectingthestatpathwayandtcellactivation
AT eldforss novelsomaticmutationsinlargegranularlymphocyticleukemiaaffectingthestatpathwayandtcellactivation
AT ellonenp novelsomaticmutationsinlargegranularlymphocyticleukemiaaffectingthestatpathwayandtcellactivation
AT olsont novelsomaticmutationsinlargegranularlymphocyticleukemiaaffectingthestatpathwayandtcellactivation
AT jereza novelsomaticmutationsinlargegranularlymphocyticleukemiaaffectingthestatpathwayandtcellactivation
AT clementemj novelsomaticmutationsinlargegranularlymphocyticleukemiaaffectingthestatpathwayandtcellactivation
AT kallioniemio novelsomaticmutationsinlargegranularlymphocyticleukemiaaffectingthestatpathwayandtcellactivation
AT porkkak novelsomaticmutationsinlargegranularlymphocyticleukemiaaffectingthestatpathwayandtcellactivation
AT heckmanc novelsomaticmutationsinlargegranularlymphocyticleukemiaaffectingthestatpathwayandtcellactivation
AT loughrantp novelsomaticmutationsinlargegranularlymphocyticleukemiaaffectingthestatpathwayandtcellactivation
AT maciejewskijp novelsomaticmutationsinlargegranularlymphocyticleukemiaaffectingthestatpathwayandtcellactivation
AT mustjokis novelsomaticmutationsinlargegranularlymphocyticleukemiaaffectingthestatpathwayandtcellactivation