The transcriptional regulator HDAC7 role in B cell development and associated malignancies

[eng] Proper B cell identity demands a tight controlled genomic and epigenomic landscape at each stage of cellular differentiation during B lymphocyte development. It has been previously identified in our group that HDAC7 is an essential regulator of early B cell development, and its absence leads t...

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Autor: Meler Marquina, Ainara
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/202962
Acceso en línea:https://hdl.handle.net/2445/202962
http://hdl.handle.net/10803/689163
Access Level:acceso abierto
Palabra clave:Epigenètica
Biologia del desenvolupament
Factors de transcripció
Limfòcits
Cèl·lules B
Histones
Epigenetics
Developmental biology
Transcription factors
Lymphocytes
B cells
id ES_697746a7f7a9bfa7ef5a2e18daee5004
oai_identifier_str oai:diposit.ub.edu:2445/202962
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv The transcriptional regulator HDAC7 role in B cell development and associated malignancies
title The transcriptional regulator HDAC7 role in B cell development and associated malignancies
spellingShingle The transcriptional regulator HDAC7 role in B cell development and associated malignancies
Meler Marquina, Ainara
Epigenètica
Biologia del desenvolupament
Factors de transcripció
Limfòcits
Cèl·lules B
Histones
Epigenetics
Developmental biology
Transcription factors
Lymphocytes
B cells
title_short The transcriptional regulator HDAC7 role in B cell development and associated malignancies
title_full The transcriptional regulator HDAC7 role in B cell development and associated malignancies
title_fullStr The transcriptional regulator HDAC7 role in B cell development and associated malignancies
title_full_unstemmed The transcriptional regulator HDAC7 role in B cell development and associated malignancies
title_sort The transcriptional regulator HDAC7 role in B cell development and associated malignancies
dc.creator.none.fl_str_mv Meler Marquina, Ainara
author Meler Marquina, Ainara
author_facet Meler Marquina, Ainara
author_role author
dc.contributor.none.fl_str_mv Parra Bola, Mª Isabel
Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació
dc.subject.none.fl_str_mv Epigenètica
Biologia del desenvolupament
Factors de transcripció
Limfòcits
Cèl·lules B
Histones
Epigenetics
Developmental biology
Transcription factors
Lymphocytes
B cells
topic Epigenètica
Biologia del desenvolupament
Factors de transcripció
Limfòcits
Cèl·lules B
Histones
Epigenetics
Developmental biology
Transcription factors
Lymphocytes
B cells
description [eng] Proper B cell identity demands a tight controlled genomic and epigenomic landscape at each stage of cellular differentiation during B lymphocyte development. It has been previously identified in our group that HDAC7 is an essential regulator of early B cell development, and its absence leads to a dramatic block at the pro-B to pre-B cell transition. In this work, we have depicted the molecular mechanisms by which HDAC7 modulates early B cell development. Specifically, HDAC7 loss induces TET2 expression, which promotes DNA 5-hydroxymethylation and chromatin de-condensation. These findings shed light on the mechanisms by which HDAC7 loss or misregulation may lead to pro-B hematological malignancies. Actually, within this work we demonstrate that HDAC7 loss in infant acute lymphoblastic leukemia of pro- B cells (pro-B-ALL) correlates with a worse prognosis. The ectopic expression of HDAC7 in pro-B-ALL cell lines leads to a transcriptional phenotype closely related to healthy B cell progenitors, highlighting its importance in the guidance of B cell identity. However, HDAC7 role in mature B cell biology and associated malignancies is unknown. We demonstrate that HDAC7 is essential for the entry and initiation of the germinal center (GC) reaction. Upon HDAC7 loss, there is a blockade of B cell development at the pre-GC stage, which leads to the generation of aberrant GC B cells, diminished class switch recombination and plasma cell formation. We observe that HDAC7 is generally underexpressed in diffuse large B cell lymphoma (DLBCL) tumors, and its low expression is associated with a poor prognosis of the patients. HDAC7 exogenous expression in DLBCL cell lines reduces its tumorigenicity. In summary, this thesis project aims to describe first, the mechanistical regulation of HDAC7 in early B cell development, and second, HDAC7 implication in terminal B cell development. Concomitantly, we intended to decipher the potential contribution of HDAC7 deregulation in pro-B-ALL and DLBCL, which are B cell derived malignancies in the pro-B and GC B cell developmental stages, respectively.
publishDate 2023
dc.date.none.fl_str_mv 2023
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 https://hdl.handle.net/2445/202962
http://hdl.handle.net/10803/689163
url https://hdl.handle.net/2445/202962
http://hdl.handle.net/10803/689163
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv (c) Meler Marquina, Ainara, 2023
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Meler Marquina, Ainara, 2023
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentació
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling The transcriptional regulator HDAC7 role in B cell development and associated malignanciesMeler Marquina, AinaraEpigenèticaBiologia del desenvolupamentFactors de transcripcióLimfòcitsCèl·lules BHistonesEpigeneticsDevelopmental biologyTranscription factorsLymphocytesB cells[eng] Proper B cell identity demands a tight controlled genomic and epigenomic landscape at each stage of cellular differentiation during B lymphocyte development. It has been previously identified in our group that HDAC7 is an essential regulator of early B cell development, and its absence leads to a dramatic block at the pro-B to pre-B cell transition. In this work, we have depicted the molecular mechanisms by which HDAC7 modulates early B cell development. Specifically, HDAC7 loss induces TET2 expression, which promotes DNA 5-hydroxymethylation and chromatin de-condensation. These findings shed light on the mechanisms by which HDAC7 loss or misregulation may lead to pro-B hematological malignancies. Actually, within this work we demonstrate that HDAC7 loss in infant acute lymphoblastic leukemia of pro- B cells (pro-B-ALL) correlates with a worse prognosis. The ectopic expression of HDAC7 in pro-B-ALL cell lines leads to a transcriptional phenotype closely related to healthy B cell progenitors, highlighting its importance in the guidance of B cell identity. However, HDAC7 role in mature B cell biology and associated malignancies is unknown. We demonstrate that HDAC7 is essential for the entry and initiation of the germinal center (GC) reaction. Upon HDAC7 loss, there is a blockade of B cell development at the pre-GC stage, which leads to the generation of aberrant GC B cells, diminished class switch recombination and plasma cell formation. We observe that HDAC7 is generally underexpressed in diffuse large B cell lymphoma (DLBCL) tumors, and its low expression is associated with a poor prognosis of the patients. HDAC7 exogenous expression in DLBCL cell lines reduces its tumorigenicity. In summary, this thesis project aims to describe first, the mechanistical regulation of HDAC7 in early B cell development, and second, HDAC7 implication in terminal B cell development. Concomitantly, we intended to decipher the potential contribution of HDAC7 deregulation in pro-B-ALL and DLBCL, which are B cell derived malignancies in the pro-B and GC B cell developmental stages, respectively.[spa] La identidad de las células B se rige por un estrecho control a nivel genético y epigenético en cada etapa de la diferenciación celular durante el desarrollo de los linfocitos B. Previamente se identificó en nuestro grupo que HDAC7 es un regulador esencial en el desarrollo temprano de células B, y su ausencia conduce a un bloqueo en la transición de las células pro-B a pre-B. En este trabajo, hemos descrito los mecanismos moleculares por los cuales HDAC7 modula el desarrollo temprano de células B. Concretamente, la pérdida de HDAC7 induce la expresión de TET2, que promueve la 5-hidroximetilación del ADN y la descompactación de la cromatina. Estos hallazgos arrojan luz sobre los mecanismos por los cuales la pérdida, o la desregulación, de HDAC7 pueden conducir a neoplasias hematológicas de células pro-B. De hecho, en este trabajo demostramos que la pérdida de HDAC7 en la leucemia linfoblástica aguda infantil de células pro-B (pro-B-ALL) se correlaciona con un peor pronóstico. La expresión ectópica de HDAC7 en líneas celulares de pro-B-ALL conduce a un fenotipo transcripcional estrechamente parecido al de células B progenitoras sanas, lo que destaca la importancia de HDAC7 en la orientación de la identidad de las células B. Sin embargo, se desconoce el papel de HDAC7 en la biología de las células B maduras y las neoplasias malignas que se le asocian. En esta tesis demostramos que HDAC7 es esencial para la entrada y el inicio de la reacción del centro germinal (CG). Tras la pérdida de HDAC7, hay un bloqueo del desarrollo de células B en la etapa previa al CG, lo que conduce a la generación de células B de CG aberrantes, a una disminución de la reacción de cambio de isotipo y a una menor producción de células plasmáticas. Observamos que HDAC7 generalmente presenta una baja expresión en pacientes con linfoma difuso de células B grandes (DLBCL), y esta baja expresión se asocia con un mal pronóstico de los pacientes. La expresión exógena de HDAC7 en líneas celulares DLBCL reduce su tumorigenicidad. En resumen, este proyecto de tesis tiene como objetivo describir, primero, la regulación mecánica de HDAC7 en el desarrollo temprano de las células B, y segundo, la implicación de HDAC7 en el desarrollo terminal de las células B. Al mismo tiempo, hemos descrito la contribución de HDAC7 en pro-B-ALL y DLBCL, que son malignidades hematológicas derivadas de células B en las etapas de desarrollo correspondientes al estadio pro-B y de CG, respectivamente.Universitat de BarcelonaParra Bola, Mª IsabelUniversitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació2023info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/202962http://hdl.handle.net/10803/689163Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentacióreponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Meler Marquina, Ainara, 2023info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2029622026-05-27T06:46:51Z
score 15,300719

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