Collins Cailin T, Hess Jay L
aDepartment of Pathology, University of Michigan, Ann Arbor, MichiganbIndiana University School of Medicine, Indianapolis, Indiana, USA.
Curr Opin Hematol. 2016 Jul;23(4):354-61. doi: 10.1097/MOH.0000000000000245.
HOXA9 is a homeodomain transcription factor that plays an essential role in normal hematopoiesis and acute leukemia, in which its overexpression is strongly correlated with poor prognosis. The present 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 overexpression 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.
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发挥重要作用，其过表达与不良预后密切相关。本综述重点介绍了在理解导致HOXA9失调的基因改变以及HOXA9介导转化的下游机制方面的最新进展。
多种基因改变，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高水平表达。导致HOXA9过表达的机制开始得到明确，并且代表了有吸引力的治疗靶点。靶向MLL融合蛋白复合体成员（如DOT1L和Menin）的小分子在动物模型中已显示出有希望的结果，并且一种DOT1L抑制剂目前正在临床试验中进行测试。HOXA9的重要辅因子和协同因子也正在被确定，包括HOXA9驱动的白血病所需的转录因子PU.1和C/EBPα。HOXA9的靶标，包括IGF1、CDX4、INK4A/INK4B/ARF、mir-21和mir-196b等许多其他靶标，为潜在的药物开发提供了另一条途径。
HOXA9失调是一大类侵袭性急性白血病的基础。了解调节HOXA9表达和活性的机制及其关键的下游靶标，有望开发出更具选择性和有效性的白血病治疗方法。
