Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis

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.

The cancer COMPASS: navigating the functions of MLL complexes in cancer

“…Mixed-lineage leukemia (MLL or MLL1, now known as KMT2A) is the founding member of the MLL family and was initially discovered more than 20 years ago (33) as being frequently associated with a subpopulation of aggressive lymphoid and myeloid leukemias (reviewed recently in Bellabio et al (34) and Somervaille et al (35)). These malignancies are known to be acute, with poor prognosis, and more common in young children than adults.…”

MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia

“…Translocations of the mixed-lineage leukemia ( MLL ) gene produce over 120 different MLL fusion proteins (MLL-FPs) that cause aggressive acute leukemias, the most common one being the MLL-AF4 fusion (Ballabio and Milne, 2012, Meyer et al., 2013). Despite much progress in the treatment of childhood leukemias, infants carrying MLL rearrangements have a very poor prognosis (Pui et al., 2011); thus, improving therapies for MLL-FP patients remains an unmet need.…”

Genetic mutations in epigenetic modifiers as therapeutic targets in acute myeloid leukemia

“…Translocations of KDM2A gene, encoded on chromosome 11q23, produce in-frame fusion proteins with several partner genes [113,114]. These chimeras may contribute to leukemic transformation through different gain-of-function mechanisms such as haploinsufficiency for wild-type KDM2A allele [115].…”