急性髓性白血病的表观遗传机制。

Antoine H F M Peters, Juerg Schwaller
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引用次数: 10

摘要

急性白血病的特点是造血干细胞和祖细胞克隆扩增,分化受阻。临床和实验证据表明,急性髓性白血病(AML)是多种功能协同的遗传改变的产物,包括染色体易位导致白血病融合蛋白的表达。一些aml相关病变靶向染色质调节因子,如组蛋白甲基转移酶或组蛋白乙酰转移酶,包括混合谱系白血病1 (MLL1)或CREB结合蛋白/p300。分子和生化研究开始为这些致白血病融合蛋白的靶向机制和作用方式提供有用的见解,这些融合蛋白导致异常的基因表达程序和AML。染色质调节机制也通过异常募集辅助抑制因子介导白血病发生的关键驱动因子的转化活动。最近的大规模筛选工作表明,异常的DNA启动子甲基化和异常表达的microrna在AML的发病机制中也起着重要作用。目前,利用表观遗传机制的潜在可逆性进行治疗的努力主要集中在抑制DNA甲基转移酶或组蛋白去乙酰化酶的小分子上。一些使用这些化合物的I/II期临床试验报告了有希望的,但大多是短暂的临床反应。这强调需要进一步剖析表观遗传机制的分子参与者,驱动白血病状态的诱导、维持和潜在的可逆性,以开发有效和持久的靶向治疗策略。
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Epigenetic mechanisms in acute myeloid leukemia.

Acute leukemia is characterized by clonal expansion of hematopoietic stem and progenitor cells with blocked differentiation. Clinical and experimental evidences suggest that acute myeloid leukemia (AML) is the product of several functionally cooperating genetic alterations including chromosomal translocations leading to expression of leukemogenic fusion proteins. Several AML-associated lesions target chromatin regulators like histone methyltransferases or histone acetyltransferases, including mixed-lineage leukemia 1 (MLL1) or CREB bindung protein/p300. Molecular and biochemical studies start to provide useful insights into the mechanisms of targeting and mode-of-action of such leukemogenic fusion proteins resulting in aberrant gene expression programs and AML. Chromatin modulating mechanisms are also mediating the transforming activity of key drivers of leukemogenesis by aberrant recruitment of corepressors. Recent large-scale screening efforts demonstrated that both aberrant DNA promoter methylation and aberrantly expressed microRNAs play an important role in the pathogenesis of AML as well. Current efforts to therapeutically exploit the potential reversibility of epigenetic mechanisms are focused on small molecules that inhibit DNA methyltransferases or histone deacetylases. Several phase I/II clinical trials using such compounds have reported promising, but mostly transient, clinical responses. This underscores the need to further dissect the molecular players of epigenetic mechanisms driving induction, maintenance, and potential reversibility of leukemic state to develop efficient and long-lasting targeted therapeutic strategies.

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