Role of epigenetic modifications in acute promyelocytic leukemia
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Di Croce, Luciano
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Villa, R. Role of epigenetic modifications in acute promyelocytic leukemia. Universitat Pompeu Fabra; 2007. handle: http://hdl.handle.net/10803/7144
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Doctoral program
Programa de doctorat en Biomedicina
Abstract
Mi trabajo ha estado enfocado en la implicación de los diferentes mecanismos epigenéticos de PML-RARa en la inducción de la leucemia promielocítica aguda (APL).<br/>En particular yo estudié el rol de MBD1, un miembro de la conservada familia de proteinas capaces de unirse al DNA metilado, demostrando que desempeña un papel importante en la progresión de la leucemia. De hecho, mostré que MBD1 es recruida por PML-RARa a sus promotores diana a través de los mecanismos mediados por HDAC3, participando por tanto en la represión transcripcional. Además, investigué hasta donde la metilación de la H3K27 mediada por Polycomb contribuye a la tumorgénesis mediada por PML-RARa. Demostré que PML-RARa dirige al PRC2 hacia el locus del tumor supresor causando la metilación de la H3K27. Fue interesante ser capaz de mostrar que tanto la metilación del DNA como la de las histonas era requerida para mantener el aberrante silencio génico. Esto apuntaba hacia una intercomunicación entre estos diferentes marcadores epigenéticos contribuyendo a la patología molecular de la leucemia. Resumiendo, estos resultados nos proporcionan elementos nuevos para comprender los mecanismos moleculares esenciales en la tumorgénesis y progresión de la APL.
My work was focused on the involvement of different epigenetic mechanisms in PML-RARa-induced acute promyelocytic leukemia (APL). In particular, I studied the role of MBD1, a member of a conserved family of proteins able to bind methylated DNA, demonstrating that has an important function in leukemia progression. Indeed, I showed that MBD1 is recruited by PML-RARa to its target promoters through an HDAC3-mediated mechanism, thus participating in transcriptional repression.. Furthermore, I investigated how far Polycomb-mediated H3K27 methylation contributes to PML-RARa mediated tumorigenesis. I demonstrated that PML-RARa targets the PRC2 to tumor suppressor loci causing H3K27 methylation. Interestingly, I was able to show that both DNA and histone methylation are required to maintain PML-RARa aberrant gene silencing, pointing towards a crosstalk among these different epigenetic layers that contributes to the molecular pathology of leukemia. In summary these results provide new insights into the molecular mechanisms underlying APL tumorigenesis and progression.
My work was focused on the involvement of different epigenetic mechanisms in PML-RARa-induced acute promyelocytic leukemia (APL). In particular, I studied the role of MBD1, a member of a conserved family of proteins able to bind methylated DNA, demonstrating that has an important function in leukemia progression. Indeed, I showed that MBD1 is recruited by PML-RARa to its target promoters through an HDAC3-mediated mechanism, thus participating in transcriptional repression.. Furthermore, I investigated how far Polycomb-mediated H3K27 methylation contributes to PML-RARa mediated tumorigenesis. I demonstrated that PML-RARa targets the PRC2 to tumor suppressor loci causing H3K27 methylation. Interestingly, I was able to show that both DNA and histone methylation are required to maintain PML-RARa aberrant gene silencing, pointing towards a crosstalk among these different epigenetic layers that contributes to the molecular pathology of leukemia. In summary these results provide new insights into the molecular mechanisms underlying APL tumorigenesis and progression.
Keywords
transcription, MBD1, methyl-CpG-binding proteins, DNA methylation, polycomb-complexes, histone methylation, HDAC3, histone acetylation/deacetylation, chromatin, epigenetics, PML-RARa, leukemia, transcripción, MBD1, proteínas que se pegan al DNA metilado, metilación del DNA, polycomb, metilación de las histonas, HDAC3, acetilación/deacetilación de las histonas, cromatina, epigénetica, PML-RARa, leucemia
Subjects
575 - General genetics. General cytogenetics. Immunogenetics. Evolution. Phylogeny
616.4 - Pathology of the lymphatic system, hematopoietic organs, endocrine organs
616.4 - Pathology of the lymphatic system, hematopoietic organs, endocrine organs
Publisher
Universitat Pompeu Fabra
