文章：

白血病的发生：不仅仅是突变基因

Leukaemogenesis: more than mutant genes

原文发布日期：2010-01-01

DOI: 10.1038/nrc2765

类型: Review Article

开放获取: 否

要点：

1. Acute leukaemias, arising from neoplastic transformation of uncommitted or partially committed haematopoietic stem cells, are characterized by recurring chromosomal aberrations and gene mutations that are crucial to disease pathogenesis.
2. The recurring chromosomal translocations in acute myeloid leukaemia (AML) result in the generation of chimeric fusion proteins that in many cases function as transcriptional regulators. These include AML1–ETO (generated by a translocation between chromosomes 8 and 21, t(8;21)); CBFB–MYH11 (generated by an inversion of chromosome 16, inv(16) or t(16;16)); PML–RARA (generated by t(15;17)); MOZ–CBP (generated by t(8;16)); MORF–CBP (generated by t(10;16)); MOZ–TIF2 (generated by inv(8)); and MLL fused with various partners (generated by t(11q23)). They contribute to leukaemogenesis, at least in part by causing transcriptional deregulation through epigenetic modifications.
3. Epigenetic modifications, including DNA methylation, DNA demethylation and histone changes, lead to the activation or repression of gene expression. Aberrant epigenetic changes occur frequently in acute leukaemias. Fusion genes resulting from chromosome translocations can be regulators or mediators of the epigenetic machinery.
4. MicroRNA (miRNA) regulation may also considerably contribute to leukaemogenesis. Some miRNAs function as oncogenes or tumour suppressor genes in acute leukaemias. miRNA signatures correlate with cytogenetic and molecular subtypes of acute leukaemias, and some miRNA signatures are associated with outcome or survival of acute leukaemias.
5. Not only do miRNAs function in an epigenetic manner by post-transcriptional regulation of target genes, but they can also be targets of the epigenetic machinery and effectors of DNA methylation and histone modifications. These functions might be involved in leukaemogenesis.
6. Although the genetic heterogeneity of acute leukaemias poses therapeutic challenges, drugs or small molecules that target components of the epigenetic machinery hold great promise in the treatment of leukaemias. The use of all-trans retinoic acid in the therapy of acute promyelocytic leukaemia is one of the best known and most successful examples of targeted therapy involved in epigenetic changes; progress has also been made in the clinical trials of histone deacetylase inhibitors and DNA methyltransferase inhibitors. However, more effective treatment strategies are needed.

要点翻译：

1. 急性白血病起源于未分化或部分分化的造血干细胞的肿瘤性转化，其特征为重现性染色体畸变和基因突变，这些改变在疾病发病机制中至关重要。
2. 急性髓系白血病（AML）中重现性染色体易位导致嵌合融合蛋白的产生，这些蛋白在许多情况下作为转录调节因子发挥作用。包括AML1–ETO（由8号和21号染色体易位t(8;21)产生）、CBFB–MYH11（由16号染色体倒位inv(16)或t(16;16)产生）、PML–RARA（由t(15;17)产生）、MOZ–CBP（由t(8;16)产生）、MORF–CBP（由t(10;16)产生）、MOZ–TIF2（由inv(8)产生）以及MLL与不同伙伴基因融合（由t(11q23)产生）。这些融合蛋白通过表观遗传修饰引起转录失调，至少部分参与了白血病的发生。
3. 表观遗传修饰包括DNA甲基化、DNA去甲基化和组蛋白修饰，可导致基因表达的激活或抑制。异常表观遗传改变在急性白血病中频繁发生。染色体易位产生的融合基因可以作为表观遗传机制的调节因子或介质。
4. MicroRNA（miRNA）调控也可能显著促进白血病发生。某些miRNA在急性白血病中起癌基因或抑癌基因作用。miRNA特征谱与急性白血病的细胞遗传学和分子亚型相关，部分miRNA特征谱与急性白血病的预后或生存率相关。
5. miRNA不仅通过靶基因的转录后调控以表观遗传方式发挥作用，本身也可成为表观遗传机制的作用靶点，并作为DNA甲基化和组蛋白修饰的效应分子。这些功能可能参与白血病发生过程。
6. 尽管急性白血病的遗传异质性给治疗带来挑战，针对表观遗传机制组分的药物或小分子在白血病治疗中前景广阔。全反式维甲酸在急性早幼粒细胞白血病治疗中的应用是表观遗传改变靶向治疗中最著名、最成功的范例之一；组蛋白去乙酰化酶抑制剂和DNA甲基转移酶抑制剂的临床试验也取得了进展。然而，仍需要更有效的治疗策略。

英文摘要：

Acute leukaemias are characterized by recurring chromosomal aberrations and gene mutations that are crucial to disease pathogenesis. It is now evident that epigenetic modifications, including DNA methylation and histone modifications, substantially contribute to the phenotype of leukaemia cells. An additional layer of epigenetic complexity is the pathogenetic role of microRNAs in leukaemias, and their key role in the transcriptional regulation of tumour suppressor genes and oncogenes. The genetic heterogeneity of acute leukaemias poses therapeutic challenges, but pharmacological agents that target components of the epigenetic machinery are promising as a component of the therapeutic arsenal for this group of diseases.

摘要翻译： 

急性白血病的特征是反复出现的染色体畸变和基因突变，这些对疾病的发病机制至关重要。目前显而易见的是，包括DNA甲基化和组蛋白修饰在内的表观遗传修饰，对白血病细胞表型的形成起着重要作用。另一层表观遗传复杂性在于microRNA在白血病中的致病作用，以及它们在抑癌基因和癌基因转录调控中的关键作用。急性白血病的遗传异质性给治疗带来了挑战，但针对表观遗传机制组分的药物作为治疗这类疾病武器库的一部分，显示出良好的前景。

原文链接：

Leukaemogenesis: more than mutant genes