Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis.
Molecular and Epigenetic Mechanisms of MLL in Human Leukemogenesis.
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DOI：
10.3390/cancers4030904
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发表时间：
2012-09-10
期刊：
影响因子：
5.2
通讯作者：
Milne TA
中科院分区：
文献类型：
--
作者：
Ballabio E;Milne TA
表观遗传学通常被定义为研究不改变潜在DNA序列的基因表达或染色体稳定性的可遗传变化。表观遗传变化是通过多种机制建立的，包括DNA甲基化、非编码rna和组蛋白特定残基的共价修饰。越来越清楚的是，不仅异常的表观遗传变化在许多人类疾病（如白血病）中很常见，而且这些变化本质上是可延展性的，因此是可以治疗的。到目前为止，基于表观遗传学的治疗主要集中在使用组蛋白去乙酰化酶（HDAC）抑制剂和DNA甲基转移酶抑制剂，它们往往对细胞中的基因调控有更普遍和广泛的影响。然而，如果一个独特的分子途径可以被确定，由表观遗传机制引起的疾病是开发更有针对性的治疗方法的绝佳候选者，这些治疗方法专注于特定的基因靶点、个体结合域或特定的酶活性。设计有效的靶向治疗取决于对表观遗传突变在疾病进展中的作用的清晰理解。混合谱系白血病（MLL）蛋白是一个重要的发育蛋白的例子，它部分通过甲基化赖氨酸4上的组蛋白3来控制基因靶点的表观遗传激活。MLL是正常发育所必需的，但在侵袭性人类白血病的一个子集中也发生突变，因此为研究表观遗传细胞记忆与人类疾病之间的联系提供了一个有用的模型。最常见的MLL突变是染色体易位，将框架中的MLL基因与伴侣基因融合，产生新的融合蛋白。在这篇综述中，我们总结了最近的研究，认为MLL融合蛋白可以通过单一分子途径发挥作用，但我们也强调了重要的数据，表明MLL介导的白血病发生背后有多种独立的机制。
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.