Deregulation of the HOXA9/MEIS1 axis in acute leukemia.
Deregulation of the HOXA9/MEIS1 axis in acute leukemia.
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DOI：
10.1097/moh.0000000000000245
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发表时间：
2016-07
影响因子：
3.2
通讯作者：
Hess JL
中科院分区：
文献类型：
--
作者：
Collins CT;Hess JL
HOXA9是一种同源结构域转录因子，在正常造血和急性白血病中起重要作用，其过表达与预后不良密切相关。这篇综述强调了最近在理解导致HOXA9解除管制的遗传改变和HOXA9介导的转化的下游机制方面的进展。多种遗传改变，包括mll易位、nup98融合、NPM1突变、CDX失调和moz融合，导致急性白血病中HOXA9的高水平表达。导致HOXA9过表达的机制开始被定义，并代表了有吸引力的治疗靶点。靶向mll融合蛋白复合物成员的小分子，如DOT1L和menin，已经在动物模型中显示出有希望的结果，并且DOT1L抑制剂目前正在临床试验中进行测试。必要的HOXA9辅助因子和合作者也正在被确定，包括转录因子PU.1和C/EBPα，它们是HOXA9驱动的白血病所必需的。HOXA9靶点包括IGF1、CDX4、INK4A/INK4B/ARF、mir-21和mir-196b等，为潜在的药物开发提供了另一条途径。HOXA9解除管制是侵袭性急性白血病的主要原因。了解调控HOXA9及其关键下游靶点的表达和活性的机制，为开发更具选择性和更有效的白血病治疗提供了希望。
HOXA9 is a homeodomain transcription factor that plays an essential role in normal hematopoiesis and acute leukemia, where its over expression is strongly correlated with poor prognosis. This review highlights recent advances in the understanding of genetic alterations leading to deregulation of HOXA9 and the downstream mechanisms of HOXA9-mediated transformation. A variety of genetic alterations including MLL-translocations, NUP98-fusions, NPM1 mutations, CDX deregulation, and MOZ-fusions lead to high level HOXA9 expression in acute leukemias. The mechanisms resulting in HOXA9 over expression are beginning to be defined and represent attractive therapeutic targets. Small molecules targeting MLL-fusion protein complex members, such as DOT1L and menin, have shown promising results in animal models, and a DOT1L inhibitor is currently being tested in clinical trials. Essential HOXA9 cofactors and collaborators are also being identified, including transcription factors PU.1 and C/EBPα, which are required for HOXA9-driven leukemia. HOXA9 targets including IGF1, CDX4, INK4A/INK4B/ARF, mir-21 and mir-196b and many others provide another avenue for potential drug development. HOXA9 deregulation underlies a large subset of aggressive acute leukemias. Understanding the mechanisms regulating the expression and activity of HOXA9, along with its critical downstream targets, shows promise for the development of more selective and effective leukemia therapies.