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，在大龄儿童和年轻人中发病率最高。尽管使用强化化疗方案改善了预后，但T-ALL在20%的儿童和50-70%的成人中仍然是致命的。我们最近与圣裘德大学达里奥·坎帕纳（Dario Campana）团队的研究表明，在t细胞发育的早期阶段，分化受阻预示着T-ALL治疗失败的风险非常高。这些病例与PI3K-AKT通路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过表达有关，这是大多数T-ALL病例的共同特征。我们现在已经证明MYC和AKT通路激活在条件斑马鱼T-ALL模型中都抑制线粒体凋亡，因此，我们的中心假设是MYC和AKT下游的凋亡阻断介导高风险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Aim 1中，我们将利用斑马鱼模型系统来测试BIM抑制在MYC和AKT激活的高风险T-ALL中细胞凋亡抵抗的程度。在Aim 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T-ALL的治疗研究，以确定和克服高危人T-ALL的细胞凋亡抵抗机制。本文所提出的工作的成功完成有望导致T-ALL细胞对化疗诱导的细胞凋亡的耐药机制的鉴定，以及克服这些的治疗策略的发展。鉴于目前的治疗方案无法治愈大多数高风险T-ALL患者，开发新的有效治疗高风险T-ALL的方法有望代表这些患者治疗的重大进展。

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.