Discovery and Targeting of Apoptosis Resistance Mechanisms in High-Risk T-ALL

描述(申请人提供)：T细胞急性淋巴细胞白血病(T-ALL)是一种未成熟T细胞前体细胞的侵袭性白血病，在年龄较大的儿童和年轻人中发病率最高。虽然强化化疗方案的使用改善了预后，但T-ALL在20%的儿童和50%-70%的成年人中仍然是致命的。我们最近的工作，以及圣裘德大学Dario Campana研究小组的工作表明，在T细胞发育的早期阶段，分化停止预示着T-ALL治疗失败的非常高的风险。这些病例与PI3K-AKT途径上调的基因表达特征有关，而PTEN缺失也预示着治疗失败。因此，T-ALL治疗失败与AKT途径激活和MYC过度表达有关，这是大多数T-ALL病例的共同特征。我们现在已经证明，在T-ALL的条件斑马鱼模型中，MYC和AKT通路的激活都抑制了线粒体的凋亡。因此，我们的中心假设是，MYC和AKT下游的凋亡阻断介导了高危T-ALL的治疗耐药。然而，MYC和AKT激活抑制线粒体凋亡的机制尚不清楚。在目标1中，我们将利用斑马鱼模型系统来测试在MYC和AKT激活的高危T-ALL中，BIM的抑制在多大程度上是导致细胞凋亡抵抗的基础。在目标2中，我们将结合生化分析和在免疫缺陷小鼠中生长的高危人类T-ALL的治疗研究，以识别和克服高危人类T-ALL的凋亡抵抗机制。这项工作的成功完成有望导致识别T-ALL细胞对化疗诱导的凋亡的耐药机制，并开发出克服这些机制的治疗策略。鉴于大多数高危T-ALL患者不能用目前的治疗方案治愈，针对高危T-ALL的新的有效疗法的开发有望代表着这些患者的重大治疗进步。 公共卫生相关性：尽管有所改善，但目前T细胞急性淋巴细胞白血病(T-ALL)的治疗在20%的儿童和50%以上的成年人中仍然失败，这些患者的预后很差。高危人类T-ALL与AKT和MYC通路的激活有关，我们已经证明这些通路阻止斑马鱼T-ALL细胞的细胞死亡，暗示这些通路与抵抗化疗诱导的细胞死亡有关。在这里，我们建议结合对人类和斑马鱼T-ALL的研究，以确定这种阻断细胞死亡的机制，并测试克服这种阻断并在高危T-ALL细胞中诱导细胞死亡的治疗策略。

DESCRIPTION (provided by applicant): T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia of immature T-cell progenitors that has a peak incidence in older children and young adults. Although the use of intensified chemotherapy regimens has improved outcomes, T-ALL remains fatal in 20% of children and 50-70% of adults. Our recent work, together with that of Dario Campana's group at St. Jude, has demonstrated that differentiation arrest at the earliest stages of T-cell development predicts a very high risk of treatment failure n T-ALL. These cases are associated with a gene expression signature implicating upregulation of the PI3K-AKT pathway, whereas PTEN deletions also predict treatment failure. Thus, T-ALL treatment failure is associated with AKT pathway activation and with MYC overexpression, a feature common to most cases of T-ALL. We have now shown that MYC and AKT pathway activation both repress mitochondrial apoptosis in a conditional zebrafish model of T-ALL Thus, our central hypothesis is that an apoptotic blockade downstream of MYC and AKT mediates treatment resistance in high-risk T-ALL. However, the mechanisms through which MYC and AKT activation repress mitochondrial apoptosis remain undefined. In Aim 1, we will exploit the zebrafish model system to test the degree to which repression of BIM underlies apoptosis resistance in high-risk T-ALL with MYC and AKT activation. In Aim 2, we will combine biochemical analyses with therapeutic studies in high-risk human T-ALLs grown in immunodeficient mice to identify and overcome mechanisms of apoptosis resistance in high-risk human T-ALL. The successful completion of the work proposed here is expected to lead to the identification of mechanisms of resistance to chemotherapy-induced apoptosis in T-ALL cells, as well as to development of therapeutic strategies to overcome these. Given that most patients with high-risk T-ALL cannot be cured with current treatment regimens, the development of novel effective therapies for high-risk T-ALL is expected to represent a major therapeutic advance for these patients. PUBLIC HEALTH RELEVANCE: Despite improvements, current therapy for T-cell acute lymphoblastic leukemia (T-ALL) continues to fail in 20% of children and more than 50% of adults, and these patients have a poor prognosis. High-risk human T-ALL is associated with activation of the AKT and MYC pathways, and we have shown that these pathways block cell death in zebrafish T-ALL cells, implicating these pathways in resistance to chemotherapy-induced cell death. Here, we propose to combine studies in human and zebrafish T-ALL to identify the mechanism underlying this blockade of cell death, and to test therapeutic strategies to overcome this blockade and induce cell death in high-risk T-ALL cells.