Department of Hematology & Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
J Cell Biochem. 2011 Feb;112(2):415-24. doi: 10.1002/jcb.22972.
A growing body of evidence has underlined the involvement of histone methyltransferases and demethylases in leukemia development. These findings can be roughly classified into two categories according to their association with leukemia. On the one hand, these histone modifiers are recruited to DNA by specific affinities of aberrantly expressed transcription factors or fusion proteins, and induce chromatin modifications to regulate target gene expression. Epigenetic regulators may function as oncogenes in this context. On the other hand, recent studies have identified inactivating mutations of some key histone modulators in myeloid malignancies and these results suggest that they act as tumor suppressors. Profound understanding of these findings in the two categories will help us consider clinical applications of epigenetic drugs. In this prospect we will review the leukemogenic mechanisms clarified by the epigenetic approach and the current findings on genetic aberrations in each methyltransferase or demethylase, and discuss the potential of medical intervention in leukemia or leukemia stem cells targeting histone modifiers.
越来越多的证据强调了组蛋白甲基转移酶和去甲基酶在白血病发生中的作用。这些发现大致可以分为两类，根据它们与白血病的关联。一方面，这些组蛋白修饰物通过异常表达的转录因子或融合蛋白的特异性亲和力被招募到 DNA 上，并诱导染色质修饰来调节靶基因表达。在这种情况下，表观遗传调节剂可能作为癌基因发挥作用。另一方面，最近的研究已经在髓系恶性肿瘤中鉴定出一些关键组蛋白调节剂的失活突变，这些结果表明它们作为肿瘤抑制因子发挥作用。深入了解这两类发现将有助于我们考虑表观遗传药物的临床应用。在这一前景下，我们将回顾通过表观遗传学方法阐明的白血病发生机制，以及每种甲基转移酶或去甲基酶的遗传异常的最新发现，并讨论针对组蛋白修饰物的白血病或白血病干细胞的医学干预的潜力。
