Differentiation Therapy of Acute Myeloid Leukaemia: Combining RAR-agonists and G-CSF.

靶向特定分子的癌症治疗的应用具有重大的前景。然而，为了应用这些治疗，需要详细了解分子靶标在细胞中如何发挥作用。我们以前使用正常血细胞的工作已经确定了两个基因（MAD 1和p27 KIP 1），这两个基因是针对视黄酸受体α的靶向治疗效果所必需的。我们建议在人类白血病小鼠模型和实验室中生长的人类白血病细胞中测试这种治疗。通过删除MAD 1和p27 KIP 1基因，我们将确定缺乏这些基因的白血病是否对靶向视黄酸受体α的治疗无效。我们还将测试靶向视黄酸受体与G-CSF（一种先前已被证明具有抗白血病活性的蛋白质）结合的治疗是否可以共同阻止白血病细胞和转基因细胞的生长。这些研究将有助于确定白血病的类别，这些类别对针对视黄酸受体的治疗有反应或无反应，以更好地靶向未来的白血病治疗。

The application of cancer treatments that target specific molecules hold significant promise. However to apply these treatments detailed knowledge is required of the how the molecular targets function in cells. Our previous work using normal blood cells has identified two genes ( MAD1 and p27KIP1 ) that are required for the effects of one such targeted treatment that is aimed at the retinoic acid receptor alpha. We propose to test this treatment in mouse models of human leukaemia and in human leukemia cells grown in the laboratory. By deleting the genes for MAD1 and p27KIP1 we will determine if leukaemias lacking these genes fail to respond to treatments targeting the retinoic acid receptor alpha. We will also test if treatments that target retinoic acid receptors in combination with G-CSF, a protein that has previously been demonstrated to have anti-leukaemic activity, can work together to block growth of leukaemic and genetically modified cells. Together these studies will help define classes of leukamias that either will or will not respond to treatments aimed at retinoic acid receptor to better target future leukemia treatments.