Studying the role of BCL2 and MYC in the pathogenesis of diffuse large B cell lymphoma

Approximately 30% of patients with diffuse large B-cell lymphoma (DLBCL) co-express BCL2 and MYC, known as double-expressor lymphomas (DEL). These lymphomas associate with poorer prognosis and response to standard-of-care R-CHOP, and a preferred therapeutic alternative has not been identified yet. T...

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Autor: Sánchez, J. (Javier)|||/items/c855568f-1ce6-42d2-a7ac-82abd9a9a106
Tipo de recurso: tesis doctoral
Fecha de publicación:2023
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/68058
Acceso en línea:https://hdl.handle.net/10171/68058
Access Level:acceso abierto
Palabra clave:Materias Investigacion::Ciencias de la Salud::Genética
Diffuse large B cell lymphoma
BCL2
MYC
B-Cell lymphomagenesis
Linfoma difuso de células B
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network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Studying the role of BCL2 and MYC in the pathogenesis of diffuse large B cell lymphoma
title Studying the role of BCL2 and MYC in the pathogenesis of diffuse large B cell lymphoma
spellingShingle Studying the role of BCL2 and MYC in the pathogenesis of diffuse large B cell lymphoma
Sánchez, J. (Javier)|||/items/c855568f-1ce6-42d2-a7ac-82abd9a9a106
Materias Investigacion::Ciencias de la Salud::Genética
Diffuse large B cell lymphoma
BCL2
MYC
B-Cell lymphomagenesis
Linfoma difuso de células B
title_short Studying the role of BCL2 and MYC in the pathogenesis of diffuse large B cell lymphoma
title_full Studying the role of BCL2 and MYC in the pathogenesis of diffuse large B cell lymphoma
title_fullStr Studying the role of BCL2 and MYC in the pathogenesis of diffuse large B cell lymphoma
title_full_unstemmed Studying the role of BCL2 and MYC in the pathogenesis of diffuse large B cell lymphoma
title_sort Studying the role of BCL2 and MYC in the pathogenesis of diffuse large B cell lymphoma
dc.creator.none.fl_str_mv Sánchez, J. (Javier)|||/items/c855568f-1ce6-42d2-a7ac-82abd9a9a106
author Sánchez, J. (Javier)|||/items/c855568f-1ce6-42d2-a7ac-82abd9a9a106
author_facet Sánchez, J. (Javier)|||/items/c855568f-1ce6-42d2-a7ac-82abd9a9a106
author_role author
dc.contributor.none.fl_str_mv Martínez-Climent, J.A. (José Ángel)
Roa-Gómez, S. (Sergio)
Dadun. Depósito Académico Digital Universidad de Navarra
dc.subject.none.fl_str_mv Materias Investigacion::Ciencias de la Salud::Genética
Diffuse large B cell lymphoma
BCL2
MYC
B-Cell lymphomagenesis
Linfoma difuso de células B
topic Materias Investigacion::Ciencias de la Salud::Genética
Diffuse large B cell lymphoma
BCL2
MYC
B-Cell lymphomagenesis
Linfoma difuso de células B
description Approximately 30% of patients with diffuse large B-cell lymphoma (DLBCL) co-express BCL2 and MYC, known as double-expressor lymphomas (DEL). These lymphomas associate with poorer prognosis and response to standard-of-care R-CHOP, and a preferred therapeutic alternative has not been identified yet. There are very interesting ongoing clinical trials to evaluate the potential of venetoclax to inhibit the anti-apoptotic protein BCL2 in high grade B cell lymphomas. Additionally, there are investigations ongoing trying to find a MYC inhibitor that can be efficiently used in the clinic without secondary effects. Here, we aimed to provide complementary preclinical in vivo evidences for these investigations, modelling this DEL-scenario in new mouse models and demonstrating that combination of anti-CD20 with BCL2 or MYC specific inhibitors can improve long-term survival in BCL2/MYC-expressor DLBCL mice. For this, we first generated and characterized three multi-transgenic mouse models and further demonstrated that it is possible to successfully recapitulate the complex progression and tumor microenvironment of DEL-DLBCL in the murine setting, recapitulating the classical genetic alterations of these patients by conditional mutagenesis at early stages of the germinal center reaction. We then demonstrated that lymphomas in these mice rapidly acquire aberrant BCL2/MYC co-expression and impair apoptosis during NF-κB-driven malignant transformation of germinal center B cells, hindering DLBCL cells sensitive to inhibition of BCL2 (with venetoclax) or MYC (with MYCi975). Then, we provided in vivo evidences that combination of venetoclax with anti-CD20-based immunotherapy can result in synergistic anti-lymphoma effects and extended overall survival of mice. Not only we demonstrated specific cell killing of BCL2/MYC co-expressing lymphoma cells in response to the combination treatment; but also, we revealed, for the first time in DLBCL, that venetoclax can promote the enrichment of activated intratumoral effector/effector memory CD8+ T cells, exhibiting additional immunomodulatory potential in the DEL-DLBCL tumor microenvironment. In addition, we demonstrated that acceleration of lymphomagenesis was evidenced when MYC expression was enforced from early stages of germinal center reaction. However, this lymphomagenesis was accompanied by the appearance of non-B-cells gastrointestinal tumors, possibly driven by the leakage of MYC expression, hence, resulting resistant to the conventional anti-CD20 immunotherapeutic regimen and to antibiotic treatment, impairing overall survival. Altogether, our results strongly support pre-clinical proof-of-concept and rationale for incorporating venetoclax to anti-CD20-based treatments to improve the outcome of aggressive DEL-DLBCL, and provide evidences for future combinations with specific MYC inhibitors, either incorporating them to the actual gold-standard R-CHOP or by dual targeting the Achilles heels of tumor cells through combined BCL2 and MYC specific inhibition. These preclinical combinations could either be performed in our murine models or in the novel 3D culture technique that we have successfully implemented here, which allows the long-term culture of lymphoma cells with its tumor microenvironment in the form of tumor spheroids and could serve as an ex vivo platform for future screening of novel therapeutic strategies in DLBCL.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-12-14
2023
2023-12-14
2023
2023-12-14
2023
2023-06-21
dc.type.none.fl_str_mv doctoral thesis
http://purl.org/coar/resource_type/c_db06
dc.type.openaire.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv https://hdl.handle.net/10171/68058
url https://hdl.handle.net/10171/68058
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universidad de Navarra
publisher.none.fl_str_mv Universidad de Navarra
dc.source.none.fl_str_mv reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra
instname:Universidad de Navarra
instname_str Universidad de Navarra
reponame_str Dadun. Depósito Académico Digital de la Universidad de Navarra
collection Dadun. Depósito Académico Digital de la Universidad de Navarra
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Studying the role of BCL2 and MYC in the pathogenesis of diffuse large B cell lymphomaSánchez, J. (Javier)|||/items/c855568f-1ce6-42d2-a7ac-82abd9a9a106Materias Investigacion::Ciencias de la Salud::GenéticaDiffuse large B cell lymphomaBCL2MYCB-Cell lymphomagenesisLinfoma difuso de células BApproximately 30% of patients with diffuse large B-cell lymphoma (DLBCL) co-express BCL2 and MYC, known as double-expressor lymphomas (DEL). These lymphomas associate with poorer prognosis and response to standard-of-care R-CHOP, and a preferred therapeutic alternative has not been identified yet. There are very interesting ongoing clinical trials to evaluate the potential of venetoclax to inhibit the anti-apoptotic protein BCL2 in high grade B cell lymphomas. Additionally, there are investigations ongoing trying to find a MYC inhibitor that can be efficiently used in the clinic without secondary effects. Here, we aimed to provide complementary preclinical in vivo evidences for these investigations, modelling this DEL-scenario in new mouse models and demonstrating that combination of anti-CD20 with BCL2 or MYC specific inhibitors can improve long-term survival in BCL2/MYC-expressor DLBCL mice. For this, we first generated and characterized three multi-transgenic mouse models and further demonstrated that it is possible to successfully recapitulate the complex progression and tumor microenvironment of DEL-DLBCL in the murine setting, recapitulating the classical genetic alterations of these patients by conditional mutagenesis at early stages of the germinal center reaction. We then demonstrated that lymphomas in these mice rapidly acquire aberrant BCL2/MYC co-expression and impair apoptosis during NF-κB-driven malignant transformation of germinal center B cells, hindering DLBCL cells sensitive to inhibition of BCL2 (with venetoclax) or MYC (with MYCi975). Then, we provided in vivo evidences that combination of venetoclax with anti-CD20-based immunotherapy can result in synergistic anti-lymphoma effects and extended overall survival of mice. Not only we demonstrated specific cell killing of BCL2/MYC co-expressing lymphoma cells in response to the combination treatment; but also, we revealed, for the first time in DLBCL, that venetoclax can promote the enrichment of activated intratumoral effector/effector memory CD8+ T cells, exhibiting additional immunomodulatory potential in the DEL-DLBCL tumor microenvironment. In addition, we demonstrated that acceleration of lymphomagenesis was evidenced when MYC expression was enforced from early stages of germinal center reaction. However, this lymphomagenesis was accompanied by the appearance of non-B-cells gastrointestinal tumors, possibly driven by the leakage of MYC expression, hence, resulting resistant to the conventional anti-CD20 immunotherapeutic regimen and to antibiotic treatment, impairing overall survival. Altogether, our results strongly support pre-clinical proof-of-concept and rationale for incorporating venetoclax to anti-CD20-based treatments to improve the outcome of aggressive DEL-DLBCL, and provide evidences for future combinations with specific MYC inhibitors, either incorporating them to the actual gold-standard R-CHOP or by dual targeting the Achilles heels of tumor cells through combined BCL2 and MYC specific inhibition. These preclinical combinations could either be performed in our murine models or in the novel 3D culture technique that we have successfully implemented here, which allows the long-term culture of lymphoma cells with its tumor microenvironment in the form of tumor spheroids and could serve as an ex vivo platform for future screening of novel therapeutic strategies in DLBCL.Universidad de NavarraMartínez-Climent, J.A. (José Ángel)Roa-Gómez, S. (Sergio)Dadun. Depósito Académico Digital Universidad de Navarra20232023-12-1420232023-12-1420232023-12-1420232023-06-21doctoral thesishttp://purl.org/coar/resource_type/c_db06info:eu-repo/semantics/doctoralThesisapplication/pdfhttps://hdl.handle.net/10171/68058reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/680582026-06-21T12:47:57Z
score 15,300724

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