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

描述（由申请人提供）：T细胞急性淋巴细胞白血病（T-ALL）是一种未成熟T细胞祖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。 尽管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%的成人中仍然是致命的。我们最近的工作，以及达里奥坎帕纳的小组在圣裘德，已经证明，分化停滞在T细胞发育的最早阶段预测一个非常高的风险，治疗失败的T-ALL。这些病例与暗示PI 3 K-AKT途径上调的基因表达特征相关，而PTEN缺失也预示着治疗失败。因此，T-ALL治疗失败与AKT通路激活和MYC过表达相关，这是大多数T-ALL病例的共同特征。 我们现在已经表明，MYC和AKT途径激活都抑制线粒体凋亡的条件性斑马鱼模型的T-ALL。因此，我们的中心假设是，细胞凋亡的封锁下游MYC和AKT介导的治疗阻力在高风险的T-ALL。 然而，MYC和AKT激活抑制线粒体凋亡的机制仍不清楚。在目标1中，我们将利用斑马鱼模型系统来测试BIM抑制在MYC和AKT激活的高危T-ALL中引起凋亡抵抗的程度。 在目标2中，我们将联合收割机生化分析与在免疫缺陷小鼠中生长的高危人类T-ALL的治疗研究相结合，以识别和克服高危人类T-ALL中的凋亡抵抗机制。成功完成这里提出的工作，预计将导致识别的机制，化疗诱导的T-ALL细胞凋亡的阻力，以及发展的治疗策略，以克服这些。鉴于大多数高危T-ALL患者无法用目前的治疗方案治愈，因此，开发针对高危T-ALL的新型有效疗法有望代表这些患者的重大治疗进展。

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.