Temporal resolution by multiomic approaches of acute myeloid leukemias

Acute myeloid leukemias (AMLs) are a type of cancer where undifferentiated myeloid cells abnormally proliferate. Such phenotype can be caused by the expression of chimeric proteins like PML-RARα and MLL-AF9. Many studies analyze the final stage of the disease, without focusing on its initiation and...

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Autor: Gamarra Figueroa, Gianni Paolo
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/690384
Acceso en línea:http://hdl.handle.net/10803/690384
Access Level:acceso embargado
Palabra clave:Leukemia
Epigenetic
Phf19
Leucemia
Epigenetica
575
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spelling Temporal resolution by multiomic approaches of acute myeloid leukemiasGamarra Figueroa, Gianni PaoloLeukemiaEpigeneticPhf19LeucemiaEpigenetica575Acute myeloid leukemias (AMLs) are a type of cancer where undifferentiated myeloid cells abnormally proliferate. Such phenotype can be caused by the expression of chimeric proteins like PML-RARα and MLL-AF9. Many studies analyze the final stage of the disease, without focusing on its initiation and development, which start from healthy blood cells. Hence, we generated in vitro leukemic models that enabled us to measure the temporal transcriptomic changes orchestrated by PML-RARα and to evaluate the impact of an altered epigenetic landscape on MLL-AF9 leukemogenesis. Firstly, we studied the importance of Klf4 downregulation for the PML-RARα immortalization process. Secondly, we studied the role of a Polycomb-associated protein, called Phf19, whose depletion in healthy hematopoietic cells, prior expression of MLL-AF9, enhanced the acquisition of more aggressive traits. These data were thoroughly compared with AML patient’s datasets, which confirmed the molecular and functional results generated with these models. This study reveals how specific transcriptomics and epigenomic programs are intimately linked with AML prognosis.Las Leucemias mieloides agudas (LMA) son un tipo de cáncer donde células indiferenciadas de tipo mieloide proliferan de forma anormal. Este fenotipo se puede originar por la expression de proteínas de fusión como PML-RARα y MLL-AF9. Varios estudios han analizado sus estadios finales, sin enfocarse en su desarrollo a partir de células hematopoyéticas sanas. Por eso hemos generado modelos de leucemia in vitro para medir, a nivel transcriptómico, los cambios guiados por la expresión del oncogén PML-RARα y para evaluar el impacto que un perfil epigenético alterado pueda tener en las leucemias MLL-AF9. En primer lugar, hemos demostrado la importancia de la inhibición de Klf4 en el proceso de inmortalización guiado por PML-RARα. Luego, hemos analizado la función de una proteína asociada al complejo de Polycomb, llamada Phf19, en el desarrollo de las leucemias MLL-AF9. Los resultados enseñan como la depleción de Phf19 en células hematopoyéticas sanas, antes de expresar MLL-AF9, esté asociada con la generación de células malignas más agresivas. Estos datos fueron luego comparados con las bases de datos de pacientes LMA, las cuales confirmaron, a nivel molecular y funcional, los resultados observados con estos modelos. Este estudio revela como programas transcriptómico y epigenéticos específicos estén íntimamente relacionados con el pronóstico de la LAM.Programa de Doctorat en BiomedicinaUniversitat Pompeu FabraDi Croce, LucianoUniversitat Pompeu Fabra. Departament de Medicina i Ciències de la Vida202420242026info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion192 p.application/pdfhttp://hdl.handle.net/10803/690384TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésL'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc/4.0/http://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/embargoedAccessoai:www.tdx.cat:10803/6903842026-06-14T12:46:07Z
dc.title.none.fl_str_mv Temporal resolution by multiomic approaches of acute myeloid leukemias
title Temporal resolution by multiomic approaches of acute myeloid leukemias
spellingShingle Temporal resolution by multiomic approaches of acute myeloid leukemias
Gamarra Figueroa, Gianni Paolo
Leukemia
Epigenetic
Phf19
Leucemia
Epigenetica
575
title_short Temporal resolution by multiomic approaches of acute myeloid leukemias
title_full Temporal resolution by multiomic approaches of acute myeloid leukemias
title_fullStr Temporal resolution by multiomic approaches of acute myeloid leukemias
title_full_unstemmed Temporal resolution by multiomic approaches of acute myeloid leukemias
title_sort Temporal resolution by multiomic approaches of acute myeloid leukemias
dc.creator.none.fl_str_mv Gamarra Figueroa, Gianni Paolo
author Gamarra Figueroa, Gianni Paolo
author_facet Gamarra Figueroa, Gianni Paolo
author_role author
dc.contributor.none.fl_str_mv Di Croce, Luciano
Universitat Pompeu Fabra. Departament de Medicina i Ciències de la Vida
dc.subject.none.fl_str_mv Leukemia
Epigenetic
Phf19
Leucemia
Epigenetica
575
topic Leukemia
Epigenetic
Phf19
Leucemia
Epigenetica
575
description Acute myeloid leukemias (AMLs) are a type of cancer where undifferentiated myeloid cells abnormally proliferate. Such phenotype can be caused by the expression of chimeric proteins like PML-RARα and MLL-AF9. Many studies analyze the final stage of the disease, without focusing on its initiation and development, which start from healthy blood cells. Hence, we generated in vitro leukemic models that enabled us to measure the temporal transcriptomic changes orchestrated by PML-RARα and to evaluate the impact of an altered epigenetic landscape on MLL-AF9 leukemogenesis. Firstly, we studied the importance of Klf4 downregulation for the PML-RARα immortalization process. Secondly, we studied the role of a Polycomb-associated protein, called Phf19, whose depletion in healthy hematopoietic cells, prior expression of MLL-AF9, enhanced the acquisition of more aggressive traits. These data were thoroughly compared with AML patient’s datasets, which confirmed the molecular and functional results generated with these models. This study reveals how specific transcriptomics and epigenomic programs are intimately linked with AML prognosis.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2026
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/10803/690384
url http://hdl.handle.net/10803/690384
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc/4.0/
info:eu-repo/semantics/embargoedAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv embargoedAccess
dc.format.none.fl_str_mv 192 p.
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
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score 15,300719

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