Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Geert Grooteplein zuid 8, 6525 GA Nijmegen, The Netherlands.
Int J Hematol. 2012 Jan;95(1):8-16. doi: 10.1007/s12185-011-0996-3. Epub 2012 Jan 11.
Until recently, the genetic aberrations that are causally linked to the pathogenesis of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms were largely unknown. Using novel technologies like high-resolution SNP-array analysis and next generation sequencing, various genes have now been identified that are recurrently mutated. Strikingly, several of the newly identified genes (ASXL1, DNMT3A, EZH2, IDH1 and IDH2, and TET2) are involved in the epigenetic regulation of gene expression. Aberrant epigenetic modifications have been described in many types of cancer, including myeloid malignancies. It has been proposed that repression of genes that are crucial for the cessation of the cell cycle and induction of differentiation might contribute to the malignant transformation of normal hematopoietic cells. Several therapies that aim to re-express silenced genes are currently being tested in MDS, like histone deacetylase inhibitors and hypomethylating agents. It will be interesting to assess whether patients carrying mutations in epigenetic regulators respond differently to these novel forms of epigenetic therapies.
直到最近，与骨髓增生异常综合征（MDS）和骨髓增殖性肿瘤发病机制相关的遗传异常在很大程度上仍是未知的。利用高分辨率 SNP 芯片分析和下一代测序等新技术，现在已经鉴定出许多经常发生突变的基因。引人注目的是，一些新鉴定的基因（ASXL1、DNMT3A、EZH2、IDH1 和 IDH2 以及 TET2）涉及基因表达的表观遗传调控。异常的表观遗传修饰已在许多类型的癌症中描述过，包括髓系恶性肿瘤。据推测，对细胞周期停止和分化诱导至关重要的基因的抑制可能导致正常造血细胞的恶性转化。目前正在 MDS 中测试几种旨在重新表达沉默基因的治疗方法，如组蛋白去乙酰化酶抑制剂和低甲基化剂。有趣的是，评估携带表观遗传调节剂突变的患者对这些新型表观遗传治疗的反应是否不同。
