Chromatin modifiers and the promise of epigenetic therapy in acute leukemia.
Chromatin modifiers and the promise of epigenetic therapy in acute leukemia.
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DOI：
10.1038/leu.2014.94
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发表时间：
2014-07
期刊：
影响因子：
11.4
通讯作者：
Nimer SD
中科院分区：
文献类型：
--
作者：
Greenblatt SM;Nimer SD
造血是一个严格调控的过程，涉及控制基因表达，指导造血干细胞和祖细胞向终末分化血细胞的转变。在白血病中，指导自我更新、分化和祖细胞扩增的过程被破坏，导致未成熟的、无功能的恶性细胞的积累。基于遗传分析、生物信息学和生物科学方面的技术进步，对这些过程的了解分阶段进行。白血病细胞的第一个细胞遗传学研究确定了产生致癌融合蛋白的染色体易位，并且最常见地影响转录调节子。随后，在编码控制细胞增殖和存活的信号转导途径调节因子的基因中发现了复发性体细胞突变。最近，甲基化和基因表达的全球变化的研究已经导致理解，转录调节因子和增殖信号通路的输出，最终受到染色质结构的影响。候选基因、全基因组和全外显子组测序研究已经在急性髓性白血病（AML）和急性淋巴细胞白血病（ALL）中鉴定了编码表观遗传修饰物的基因中的复发性体细胞突变。与白血病发生的两次打击模型相反，新出现的证据表明，这些表观遗传修饰剂代表了一类对白血病发展至关重要的突变，并影响各种其他致癌途径的调节。在这篇综述中，我们讨论了在白血病中发现的表观遗传修饰剂的复发性体细胞突变的范围，以及这些修饰剂如何与导致细胞分化受损和异常自我更新和增殖的经典致白血病途径相关。
Hematopoiesis is a tightly regulated process involving the control of gene expression that directs the transition from hematopoietic stem and progenitor cells to terminally differentiated blood cells. In leukemia, the processes directing self-renewal, differentiation, and progenitor cell expansion are disrupted, leading to the accumulation of immature, non-functioning malignant cells. Insights into these processes have come in stages, based upon technological advances in genetic analyses, bioinformatics, and biological sciences. The first cytogenetic studies of leukemic cells identified chromosomal translocations that generate oncogenic fusion proteins, and most commonly affect regulators of transcription. This was followed by the discovery of recurrent somatic mutations in genes encoding regulators of the signal transduction pathways that control cell proliferation and survival. Recently, studies of global changes in methylation and gene expression have led to the understanding that the output of transcriptional regulators and the proliferative signaling pathways, are ultimately influenced by chromatin structure. Candidate gene, whole genome, and whole exome sequencing studies have identified recurrent somatic mutations in genes encoding epigenetic modifiers in both acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). In contrast to the two hit model of leukemogenesis, emerging evidence suggests that these epigenetic modifiers represent a class of mutations that are critical to the development of leukemia and affect the regulation of various other oncogenic pathways. In this review, we discuss the range of recurrent, somatic mutations in epigenetic modifiers found in leukemia and how these modifiers relate to the classical leukemogenic pathways that lead to impaired cell differentiation and aberrant self-renewal and proliferation.
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影响因子：
30.8
作者：
Busque L;Patel JP;Figueroa ME;Vasanthakumar A;Provost S;Hamilou Z;Mollica L;Li J;Viale A;Heguy A;Hassimi M;Socci N;Bhatt PK;Gonen M;Mason CE;Melnick A;Godley LA;Brennan CW;Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
影响因子：
64.8
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50.3
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通讯作者：
Levine RL
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
64.8
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
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