Molecular characterization of the microenvironment in CLL-like monoclonal B cell lymphocytosis and early-stage chronic lymphocytic leukemia

The analysis of the microenvironment in CLL-like monoclonal B cell lymphocytosis (MBL) and early-stage chronic lymphocytic leukemia (CLL) is relevant for understanding the natural history of CLL. To this end, a total of 58 MBL, 54 early-stage CLL and 31 healthy subjects were extensively characterize...

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Autor: Blanco Ares, Gonzalo
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/664506
Acceso en línea:http://hdl.handle.net/10803/664506
Access Level:acceso abierto
Palabra clave:Chronic lymphocytic leukemia (CLLl)
CLL-like monoclonal B cell lymphocytosis (MBL)
Tumor microenvironment (TME)
Inflammatory response
Leucemia linfàtica crónica (LLC)
Linfocitosis B monoclonal (LBM) de tipo LLC
Microambiente tumoral
Respuesta inflamatoria
577
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network_name_str España
repository_id_str
dc.title.none.fl_str_mv Molecular characterization of the microenvironment in CLL-like monoclonal B cell lymphocytosis and early-stage chronic lymphocytic leukemia
title Molecular characterization of the microenvironment in CLL-like monoclonal B cell lymphocytosis and early-stage chronic lymphocytic leukemia
spellingShingle Molecular characterization of the microenvironment in CLL-like monoclonal B cell lymphocytosis and early-stage chronic lymphocytic leukemia
Blanco Ares, Gonzalo
Chronic lymphocytic leukemia (CLLl)
CLL-like monoclonal B cell lymphocytosis (MBL)
Tumor microenvironment (TME)
Inflammatory response
Leucemia linfàtica crónica (LLC)
Linfocitosis B monoclonal (LBM) de tipo LLC
Microambiente tumoral
Respuesta inflamatoria
577
title_short Molecular characterization of the microenvironment in CLL-like monoclonal B cell lymphocytosis and early-stage chronic lymphocytic leukemia
title_full Molecular characterization of the microenvironment in CLL-like monoclonal B cell lymphocytosis and early-stage chronic lymphocytic leukemia
title_fullStr Molecular characterization of the microenvironment in CLL-like monoclonal B cell lymphocytosis and early-stage chronic lymphocytic leukemia
title_full_unstemmed Molecular characterization of the microenvironment in CLL-like monoclonal B cell lymphocytosis and early-stage chronic lymphocytic leukemia
title_sort Molecular characterization of the microenvironment in CLL-like monoclonal B cell lymphocytosis and early-stage chronic lymphocytic leukemia
dc.creator.none.fl_str_mv Blanco Ares, Gonzalo
author Blanco Ares, Gonzalo
author_facet Blanco Ares, Gonzalo
author_role author
dc.contributor.none.fl_str_mv Espinet Solà, Blanca
Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut
dc.subject.none.fl_str_mv Chronic lymphocytic leukemia (CLLl)
CLL-like monoclonal B cell lymphocytosis (MBL)
Tumor microenvironment (TME)
Inflammatory response
Leucemia linfàtica crónica (LLC)
Linfocitosis B monoclonal (LBM) de tipo LLC
Microambiente tumoral
Respuesta inflamatoria
577
topic Chronic lymphocytic leukemia (CLLl)
CLL-like monoclonal B cell lymphocytosis (MBL)
Tumor microenvironment (TME)
Inflammatory response
Leucemia linfàtica crónica (LLC)
Linfocitosis B monoclonal (LBM) de tipo LLC
Microambiente tumoral
Respuesta inflamatoria
577
description The analysis of the microenvironment in CLL-like monoclonal B cell lymphocytosis (MBL) and early-stage chronic lymphocytic leukemia (CLL) is relevant for understanding the natural history of CLL. To this end, a total of 58 MBL, 54 early-stage CLL and 31 healthy subjects were extensively characterized by various immunological and molecular methods. Purified CD4+ and CD8+ mononuclear cells from peripheral blood were subjected to gene expression studies and T cell receptor (TR) repertoire analysis, whereas cytokine immunoassays were performed in serum samples. Gene expression studies in CD4+ cells revealed increased cytotoxic and inflammatory pathways, which were higher in MBL than in early-stage CLL. Gene dysregulation was not remarkable in CD8+ cells. Increased serum levels of cytokines such as IL8, IFNγ and TNFα were also observed in MBL, while early-stage CLL generally displayed lower cytokine levels, especially amongst cases bearing somatically hypermutated IGHV genes. TR analysis demonstrated oligoclonality in both entities with persisting T cell clones over time and increasing clonality within CD4+ T cells concurrently with the expansion of neoplastic B cells. Besides, identical T cell clonotypes were identified in different MBL/CLL cases. All these findings implicate inflammatory processes and antigenic elements in the immune background of CLL, whose effects are significantly altered during progression from MBL to CLL.
publishDate 2017
dc.date.none.fl_str_mv 2017
2018
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/664506
url http://hdl.handle.net/10803/664506
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 178 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat Pompeu Fabra
publisher.none.fl_str_mv Universitat Pompeu Fabra
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869405447791837184
spelling Molecular characterization of the microenvironment in CLL-like monoclonal B cell lymphocytosis and early-stage chronic lymphocytic leukemiaBlanco Ares, GonzaloChronic lymphocytic leukemia (CLLl)CLL-like monoclonal B cell lymphocytosis (MBL)Tumor microenvironment (TME)Inflammatory responseLeucemia linfàtica crónica (LLC)Linfocitosis B monoclonal (LBM) de tipo LLCMicroambiente tumoralRespuesta inflamatoria577The analysis of the microenvironment in CLL-like monoclonal B cell lymphocytosis (MBL) and early-stage chronic lymphocytic leukemia (CLL) is relevant for understanding the natural history of CLL. To this end, a total of 58 MBL, 54 early-stage CLL and 31 healthy subjects were extensively characterized by various immunological and molecular methods. Purified CD4+ and CD8+ mononuclear cells from peripheral blood were subjected to gene expression studies and T cell receptor (TR) repertoire analysis, whereas cytokine immunoassays were performed in serum samples. Gene expression studies in CD4+ cells revealed increased cytotoxic and inflammatory pathways, which were higher in MBL than in early-stage CLL. Gene dysregulation was not remarkable in CD8+ cells. Increased serum levels of cytokines such as IL8, IFNγ and TNFα were also observed in MBL, while early-stage CLL generally displayed lower cytokine levels, especially amongst cases bearing somatically hypermutated IGHV genes. TR analysis demonstrated oligoclonality in both entities with persisting T cell clones over time and increasing clonality within CD4+ T cells concurrently with the expansion of neoplastic B cells. Besides, identical T cell clonotypes were identified in different MBL/CLL cases. All these findings implicate inflammatory processes and antigenic elements in the immune background of CLL, whose effects are significantly altered during progression from MBL to CLL.El estudio del microambiente en la linfocitosis B monoclonal (LBM) de tipo LLC y en estadios iniciales de la leucemia linfática crónica (LLC) tiene gran relevancia para entender la historia natural de la enfermedad. Con este objetivo se caracterizaron 58 casos de LBM, 54 de LLC en fases iniciales y 31 sujetos sanos. Se analizó la expresión génica y el repertorio del receptor de células T (TR) en fracciones de células mononucleares CD4+ y CD8+ purificadas a partir de sangre periférica. Además, se realizaron inmunoensayos para medir niveles de citoquinas en suero. Los estudios de expresión génica revelaron patrones citotóxicos e inflamatorios aumentados en células CD4+, superiores en LBM con respecto a LLC en fases iniciales. En las células CD8+ no se observó ninguna disfunción remarcable en la expresión génica. Se detectaron niveles aumentados de citoquinas como IL8, IFNγ y TNFα en sueros de sujetos con LBM, mientras que en LLC en fases iniciales los niveles de citoquinas fueron generalmente inferiores, principalmente debido a los casos con hipermutaciones del gen IGHV. El análisis del TR mostró la existencia de oligoclonalidad en ambas entidades y de clones T persistentes en el tiempo, así como niveles de clonalidad en la fracción T CD4+ que aumentan conjuntamente con la expansión de las células B malignas. Asimismo, se identificaron clonotipos comunes en diferentes casos con LBM/LLC. Todos estos hallazgos implican un papel clave de los procesos inflamatorios y de los elementos antigénicos desde las etapas más tempranas de la enfermedad, cuyos efectos varían notablemente durante la progresión desde LBM a LLC.Programa de doctorat en BiomedicinaUniversitat Pompeu FabraEspinet Solà, BlancaUniversitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut201820192017info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion178 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/664506TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6645062026-06-14T12:46:07Z
score 15,30478

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