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Cancers 2012, 4(3), 904-944; doi:10.3390/cancers4030904
Review

Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis

 and *
Received: 2 August 2012; in revised form: 31 August 2012 / Accepted: 4 September 2012 / Published: 10 September 2012
(This article belongs to the Special Issue Leukemia)
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Abstract: 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.
Keywords: MLL; epigenetics; leukemia; super elongation complex; transcription; microRNAs MLL; epigenetics; leukemia; super elongation complex; transcription; microRNAs
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Ballabio, E.; Milne, T.A. Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis. Cancers 2012, 4, 904-944.

AMA Style

Ballabio E, Milne TA. Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis. Cancers. 2012; 4(3):904-944.

Chicago/Turabian Style

Ballabio, Erica; Milne, Thomas A. 2012. "Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis." Cancers 4, no. 3: 904-944.


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