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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| Formato: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/202962 |
| Acesso em linha: | https://hdl.handle.net/2445/202962 http://hdl.handle.net/10803/689163 |
| Access Level: | acceso abierto |
| Palavra-chave: | Epigenètica Biologia del desenvolupament Factors de transcripció Limfòcits Cèl·lules B Histones Epigenetics Developmental biology Transcription factors Lymphocytes B cells |
| Resumo: | [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. |
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