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Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis

Epigenetics is often defined as the study of heritable changes in gene expression or chromosome stability that don’t alter the underlying DNA sequence. Epigenetic changes are established through multiple mechanisms that include DNA methylation, non-coding RNAs and the covalent modification of specif...

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Autores principales: Ballabio, Erica, Milne, Thomas A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712720/
https://www.ncbi.nlm.nih.gov/pubmed/24213472
http://dx.doi.org/10.3390/cancers4030904
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author Ballabio, Erica
Milne, Thomas A.
author_facet Ballabio, Erica
Milne, Thomas A.
author_sort Ballabio, Erica
collection PubMed
description Epigenetics is often defined as the study of heritable changes in gene expression or chromosome stability that don’t alter the underlying DNA sequence. Epigenetic changes are established through multiple mechanisms that include DNA methylation, non-coding RNAs and the covalent modification of specific residues on histone proteins. It is becoming clear not only that aberrant epigenetic changes are common in many human diseases such as leukemia, but that these changes by their very nature are malleable, and thus are amenable to treatment. Epigenetic based therapies have so far focused on the use of histone deacetylase (HDAC) inhibitors and DNA methyltransferase inhibitors, which tend to have more general and widespread effects on gene regulation in the cell. However, if a unique molecular pathway can be identified, diseases caused by epigenetic mechanisms are excellent candidates for the development of more targeted therapies that focus on specific gene targets, individual binding domains, or specific enzymatic activities. Designing effective targeted therapies depends on a clear understanding of the role of epigenetic mutations during disease progression. The Mixed Lineage Leukemia (MLL) protein is an example of a developmentally important protein that controls the epigenetic activation of gene targets in part by methylating histone 3 on lysine 4. MLL is required for normal development, but is also mutated in a subset of aggressive human leukemias and thus provides a useful model for studying the link between epigenetic cell memory and human disease. The most common MLL mutations are chromosome translocations that fuse the MLL gene in frame with partner genes creating novel fusion proteins. In this review, we summarize recent work that argues MLL fusion proteins could function through a single molecular pathway, but we also highlight important data that suggests instead that multiple independent mechanisms underlie MLL mediated leukemogenesis.
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spelling pubmed-37127202013-08-05 Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis Ballabio, Erica Milne, Thomas A. Cancers (Basel) Review Epigenetics is often defined as the study of heritable changes in gene expression or chromosome stability that don’t alter the underlying DNA sequence. Epigenetic changes are established through multiple mechanisms that include DNA methylation, non-coding RNAs and the covalent modification of specific residues on histone proteins. It is becoming clear not only that aberrant epigenetic changes are common in many human diseases such as leukemia, but that these changes by their very nature are malleable, and thus are amenable to treatment. Epigenetic based therapies have so far focused on the use of histone deacetylase (HDAC) inhibitors and DNA methyltransferase inhibitors, which tend to have more general and widespread effects on gene regulation in the cell. However, if a unique molecular pathway can be identified, diseases caused by epigenetic mechanisms are excellent candidates for the development of more targeted therapies that focus on specific gene targets, individual binding domains, or specific enzymatic activities. Designing effective targeted therapies depends on a clear understanding of the role of epigenetic mutations during disease progression. The Mixed Lineage Leukemia (MLL) protein is an example of a developmentally important protein that controls the epigenetic activation of gene targets in part by methylating histone 3 on lysine 4. MLL is required for normal development, but is also mutated in a subset of aggressive human leukemias and thus provides a useful model for studying the link between epigenetic cell memory and human disease. The most common MLL mutations are chromosome translocations that fuse the MLL gene in frame with partner genes creating novel fusion proteins. In this review, we summarize recent work that argues MLL fusion proteins could function through a single molecular pathway, but we also highlight important data that suggests instead that multiple independent mechanisms underlie MLL mediated leukemogenesis. MDPI 2012-09-10 /pmc/articles/PMC3712720/ /pubmed/24213472 http://dx.doi.org/10.3390/cancers4030904 Text en © 2012 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Review
Ballabio, Erica
Milne, Thomas A.
Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis
title Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis
title_full Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis
title_fullStr Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis
title_full_unstemmed Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis
title_short Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis
title_sort molecular and epigenetic mechanisms of mll in human leukemogenesis
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712720/
https://www.ncbi.nlm.nih.gov/pubmed/24213472
http://dx.doi.org/10.3390/cancers4030904
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