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.
Highlights
Genome wide association studies provide a wealth of information on cancer driver mutations as well as revealing the incredible range of genetic diversity in human cancers [1]
This indicates that the expression of Mixed Lineage Leukemia (MLL)-FPs is sufficient for the promotion of leukemogenesis, likely through the epigenetic activation of key master regulatory factors that set up gene expression networks responsible for cell growth and proliferation
MLL fusion proteins (MLL-FPs) leukemias appear to be relatively simple from a genetic point of view, this masks a great deal of complexity on the protein, gene expression and epigenetic levels
Summary
Genome wide association studies provide a wealth of information on cancer driver mutations as well as revealing the incredible range of genetic diversity in human cancers [1]. Post-translational modifications of histone proteins are considered to be one of the epigenetic mechanisms that multicellular organisms use in order to guarantee tight spatial and temporal expression of key genes during development and differentiation [19,20,21] These modifications include “marks” such as phosphorylation (P), acetylation (Ac), methylation (Me, which can be added as a mono (1), di (2) or tri (3) methyl mark) and ubiquitination (Ub) which function by recruiting and/or stabilizing specific effector proteins ( referred to as “reader” proteins) [22]. Some of the molecular data assembled to identify and analyze recent epigenetic inhibitors has come from the analysis of MLL-FP leukemias [14,15,16] This suggests that MLL provides a useful model for studying the link between epigenetic cell memory and human disease and may provide information on pathways and targets that are more generally applicable to a wider range of different cancers
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