Clin Epigenetics. 2011 Aug;2(2):197-212. doi: 10.1007/s13148-011-0050-6. Epub 2011 Jul 9.
The myeloproliferative neoplasms (MPNs) are a group of clonal hematological malignancies characterized by a hypercellular bone marrow and a tendency to develop thrombotic complications and to evolve to myelofibrosis and acute leukemia. Unlike chronic myelogenous leukemia, where a single disease-initiating genetic event has been identified, a more complicated series of genetic mutations appear to be responsible for the BCR-ABL1-negative MPNs which include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Recent studies have revealed a number of epigenetic alterations that also likely contribute to disease pathogenesis and determine clinical outcome. Increasing evidence indicates that alterations in DNA methylation, histone modification, and microRNA expression patterns can collectively influence gene expression and potentially contribute to MPN pathogenesis. Examples include mutations in genes encoding proteins that modify chromatin structure (EZH2, ASXL1, IDH1/2, JAK2V617F, and IKZF1) as well as epigenetic modification of genes critical for cell proliferation and survival (suppressors of cytokine signaling, polycythemia rubra vera-1, CXC chemokine receptor 4, and histone deacetylase (HDAC)). These epigenetic lesions serve as novel targets for experimental therapeutic interventions. Clinical trials are currently underway evaluating HDAC inhibitors and DNA methyltransferase inhibitors for the treatment of patients with MPNs.
骨髓增殖性肿瘤（MPN）是一组克隆性血液病恶性肿瘤，其特征为骨髓过度增生，且易发生血栓并发症，并向骨髓纤维化和急性白血病发展。与慢性髓系白血病不同，后者存在单一的疾病起始遗传事件，似乎更复杂的一系列遗传突变负责 BCR-ABL1 阴性的 MPN，包括真性红细胞增多症、原发性血小板增多症和原发性骨髓纤维化。最近的研究揭示了许多表观遗传改变，这些改变也可能有助于疾病的发病机制并决定临床结果。越来越多的证据表明，DNA 甲基化、组蛋白修饰和 microRNA 表达模式的改变可以共同影响基因表达，并可能有助于 MPN 的发病机制。例如，编码改变染色质结构的蛋白的基因突变（EZH2、ASXL1、IDH1/2、JAK2V617F 和 IKZF1）以及对细胞增殖和存活至关重要的基因的表观遗传修饰（细胞因子信号抑制因子、真性红细胞增多症-1、CXC 趋化因子受体 4 和组蛋白脱乙酰酶（HDAC））。这些表观遗传病变可作为实验治疗干预的新靶点。目前正在进行临床试验，评估组蛋白去乙酰化酶抑制剂和 DNA 甲基转移酶抑制剂治疗 MPN 患者的疗效。
