Evolutionarily Conserved Signaling Pathways: Acting in the Shadows of Acute Myelogenous Leukemia's Genetic Diversity
Evolutionarily Conserved Signaling Pathways: Acting in the Shadows of Acute Myelogenous Leukemia's Genetic Diversity
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DOI：
10.1158/1078-0432.ccr-14-1436
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发表时间：
2015-01-15
影响因子：
11.5
通讯作者：
Fischer, Thomas
中科院分区：
文献类型：
--
作者：
Heidel, Florian H.;Arreba-Tutusaus, Patricia;Fischer, Thomas
急性髓细胞性白血病干细胞（AML-LSC）产生白血病群体并维持疾病。复发可能由残留LSC引起，与AML原液相比，残留LSC具有不同的敏感性和依赖性。AML-LSC由遗传和表观基因组变化驱动，这些改变影响预后和克隆选择。针对这些分子畸变的疗法已经开发出来，并在高级临床试验中显示出有希望的反应;然而，到目前为止，LSC的成功有限。除了遗传多样性之外，AML-LSC还受到微环境的严重影响，最近出现了第三个关键方面：一组进化上保守的信号传导途径，如经典的Wnt信号传导，Notch信号传导或Hedgehog通路对于维持AML-LSC是必不可少的，但对于正常的造血干细胞可能是多余的。此外，早期的报告表明细胞极性的调节剂也可能影响造血干细胞和AML生物学。这些途径之间的相互作用最近已被调查，并提出了一个网络的信号通路参与调节自我更新和致癌应激反应。在这里，我们回顾了最近发现的AML-LSC相关的进化保守途径的调节可能为消除残留疾病的新治疗方法提供机会。(C)2015年AACR。
Acute myelogenous leukemia stem cells (AML-LSC) give rise to the leukemic bulk population and maintain disease. Relapse can arise from residual LSCs that have distinct sensitivity and dependencies when compared with the AML bulk. AML-LSCs are driven by genetic and epigenomic changes, and these alterations influence prognosis and clonal selection. Therapies targeting these molecular aberrations have been developed and show promising responses in advanced clinical trials; however, so far success with LSCs has been limited. Besides the genetic diversity, AML-LSCs are critically influenced by the microenvironment, and a third crucial aspect has recently come to the fore: A group of evolutionarily conserved signaling pathways such as canonical Wnt signaling, Notch signaling, or the Hedgehog pathway can be essential for maintenance of AML-LSC but may be redundant for normal hematopoietic stem cells. In addition, early reports suggest also regulators of cell polarity may also influence hematopoietic stem cells and AML biology. Interactions between these pathways have been investigated recently and suggest a network of signaling pathways involved in regulation of self-renewal and response to oncogenic stress. Here, we review how recent discoveries on regulation of AML-LSC-relevant evolutionarily conserved pathways may open opportunities for novel treatment approaches eradicating residual disease. (C) 2015 AACR.