Epigenetic alterations in hematopoietic malignancies
Epigenetic alterations in hematopoietic malignancies
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DOI：
10.1007/s12185-012-1181-z
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发表时间：
2012-10-01
影响因子：
2.1
通讯作者：
Abdel-Wahab, Omar
中科院分区：
文献类型：
--
作者：
Chung, Young Rock;Schatoff, Emma;Abdel-Wahab, Omar
在造血系统恶性肿瘤患者中的基因发现工作已经将被认为参与基因转录的表观遗传调节的基因中的一系列突变带到了最前沿。这些突变发生在已知或怀疑在修饰DNA上的胞嘧啶核苷酸和/或改变组蛋白修饰状态中起作用的基因中。基因如ASXL 1、DNMT 3A、EZH 2、IDH 1/2、MLL 1和TET 2都已被证明在骨髓恶性肿瘤患者中发生突变和/或易位。有趣的是，在骨髓恶性肿瘤中影响DNA胞嘧啶修饰的许多改变（DNMT 3A，IDH 1/2和TET 2突变）也在T细胞淋巴瘤患者中发现，EZH 2突变似乎在T细胞急性淋巴细胞白血病的发展中也很关键。此外，在B细胞淋巴瘤中CREBBP、EP 300、EZH 2和MLL 2的频繁突变的发现表明，表观遗传改变在淋巴瘤发生中起关键作用。这篇综述的目的是提出这些表观遗传修饰剂的改变如何促进造血转化的功能证据。从这些数据中得出的结论对于理解生物学机制和潜在的治疗靶点是有价值的。
Gene discovery efforts in patients with hematopoietic malignancies have brought to the forefront a series of mutations in genes thought to be involved in the epigenetic regulation of gene transcription. These mutations occur in genes known, or suspected, to play a role in modifying cytosine nucleotides on DNA and/or altering the state of histone modifications. Genes such as ASXL1, DNMT3A, EZH2, IDH1/2, MLL1, and TET2 all have been shown to be mutated and/or translocated in patients with myeloid malignancies. Intriguingly, many of the alterations affecting DNA cytosine modifications in myeloid malignancies (mutations in DNMT3A, IDH1/2, and TET2) have also been found in patients with T-cell lymphomas, and EZH2 mutations appear to be critical in T-cell acute lymphoblastic leukemia development as well. In addition, the discovery of frequent mutations in CREBBP, EP300, EZH2, and MLL2 in B-cell lymphomas suggests that epigenetic alterations play a critical role in lymphomagenesis. The purpose of this review is to present functional evidence of how alterations in these epigenetic modifiers promote hematopoietic transformation. The conclusions drawn from these data are valuable in understanding biological mechanisms and potential therapeutic targets.