FLT3 Tyrosine Kinase Inhibitors as Therapy for Leukemia

描述(申请人提供)：我们的长期目标是提高白血病患者的治愈率，减少化疗相关的毒性。Flt3是一种受体酪氨酸激酶，是急性髓系白血病中最常见的突变基因之一，在ALL中突变频率也较低。这些突变导致Flt3激酶活性的结构性激活，有助于正常造血细胞的转化。突变患者的结果特别差，在儿童和成人人群中的治愈率在10%-20%的范围内。虽然已知有几种基因改变(主要是涉及转录因子的易位)与Flt3突变一起发生，但大多数Flt3突变发生在核型正常的患者中。在这些与Flt3合作的患者中，很可能还有其他的第二次“命中”，但这些基因可能受到细胞遗传学无法识别的点突变或小片段缺失或插入的影响。发现其中一些基因的一种方法是确定在白血病发生中与Flt3/ITD突变协同作用的基因谱。我们将遵循逆转录病毒插入突变(RIM)策略，在我们设计的表达Flt3/ITD突变的小鼠中进行。我们还将设计一只表达Flt3激活域突变的小鼠，并采用一种平行的方法来查看白血病的表型和协同作用的基因谱是否重叠，但不同于Flt3/ITD结果，因为具有KD突变的AML患者的行为与具有ITD突变的AML患者的行为不同。然后，我们将筛选具有正常细胞遗传学的Flt3突变白血病患者的样本，以确定这些基因是否存在突变或上调。我们还将评估在两种类型的突变的Flt3小鼠中发展起来的白血病对Flt3酪氨酸激酶抑制剂(TKI)的反应。最后，我们将确定可用的Flt3TKI针对已报告的患者中许多不同类型的KD突变的活性谱。研究人员描述：Flt3基因是急性髓系白血病中最常见的突变基因，具有该突变的患者治愈的机会很小。我们正在研究这些突变如何与其他基因的变化相结合，导致正常血细胞发生白血病。这将使我们能够在分子水平上更好地攻击这些白血病，提高治愈的机会，减少化疗的毒性。

DESCRIPTION (provided by applicant): Our long-term goals are to increase the cure rate and decrease chemotherapy-related toxicity for patients with leukemia. FLT3 is a receptor tyrosine kinase that is one of the most frequently mutated genes in acute myeloid leukemia and is also less frequently mutated in ALL. The mutations result in constitutive activation of the kinase activity of FLT3 that contributes to transformation of normal hematopoietic cells. The group of patients with mutations has particularly poor outcomes with cure rates in the 10-20% range in pediatric and adult populations. While there are several gene alterations (mostly translocations involving transcription factors) known to occur together with FLT3 mutations, most FLT3 mutations occur in patients with normal karyotypes. It is likely that there are other second "hits" in these patients cooperating with FLT3 but the genes are likely affected by point mutations or small deletions or insertions that are not recognized by cytogenetics. One way to discover some of these genes is to determine the spectrum of genes that can cooperate with FLT3/ITD mutations in leukemogenesis. We will follow a strategy of retroviral insertion mutagenesis (RIM) in mice that we have engineered to express a FLT3/ITD mutation. We will also engineer a mouse that expresses a FLT3 kinase domain mutation and take a parallel approach to see if the phenotype of leukemia that results and spectrum of genes that cooperate are overlapping but different from the FLT3/ITD results as the behavior of AML patients with KD mutations is different from those with ITD mutations. We will then screen samples from patients with FLT3 mutant leukemias with normal cytogenetics for the presence of mutations or upregulation of these genes. We will also assess the response of the leukemias that develop in both types of mutant FLT3 mice to FLT3 tyrosine kinase inhibitors (TKI). Finally, we will determine the spectrum of activity of available FLT3 TKI against the many different types of KD mutations that have been reported in patients. Lay description: FLT3 is the most frequently mutated gene in acute myeloid leukemia and patients with this mutation have little chance for cure. We are studying how these mutations combine with alterations in other genes to cause normal blood cells to become leukemic. This will enable us to better attack these leukemias at the molecular level to improve the chance of cure and decrease the toxicities of chemotherapy.