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

高危 T-ALL 细胞凋亡抵抗机制的发现和靶向

• 批准号: 8288545
• 负责人: Alejandro Gutierrez
• 金额: $ 18.92万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288545
• 关键词: Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Adult; Apoptosis; Apoptotic; BCL2 gene; BCL2L11 gene; Biochemical; Biological Models; Bypass; Cell Death; Cells; Chemotherapy-Oncologic Procedure; Child; Clinical Trials; Development; Disease; Family member; Gene Expression Profile; Genetic; Goals; Human; Immunodeficient Mouse; Incidence; Investigation; Knowledge; Lead; Mediating; Mitochondria; Modeling; Oncogenes; Outcome; PTEN gene; Pathway interactions; Patients; Peptides; Proto-Oncogene Proteins c-akt; Repression; Resistance; Saint Jude Children' s Research Hospital; Sampling; Staging; T cell therapy; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Treatment Failure; Treatment Protocols; Up-Regulation; Work; Zebrafish; chemotherapy; design; effective therapy; high risk; improved; leukemia; lymphoblast; novel; outcome forecast; overexpression; progenitor; resistance mechanism; small molecule; therapeutic development; therapy resistant; young adult

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.

描述（由申请人提供）：T细胞急性淋巴细胞白血病（T-All）是未成熟T细胞祖细胞的侵略性白血病，在大儿童和年轻人中有峰值的发生率。 尽管使用增强的化学疗法方案有改善的结果，但T-All在20％的儿童和50-70％的成年人中仍然致命。我们最近的工作以及达里奥·坎帕纳（Dario Campana）在圣裘德（St. Jude）的小组的工作表明，在T细胞开发的最早阶段的差异化逮捕预测，治疗失败的风险很高。这些病例与涉及PI3K-AKT途径上调的基因表达信号有关，而PTEN缺失也可以预测治疗失败。因此，T-ALL治疗失败与AKT途径激活和MYC过表达有关，MYC过表达是大多数T-ALL情况的共同特征。 现在，我们已经表明，MYC和AKT途径激活都在T-all的条件斑马鱼模型中抑制线粒体凋亡，因此，我们的中心假设是MYC下游的凋亡阻滞和Akt介导了高风险T-A​​ll中的治疗耐药性。 但是，MYC和AKT激活抑制线粒体细胞凋亡的机制仍然不确定。在AIM 1中，我们将利用斑马鱼模型系统来测试BIM抑制在高危T-All中使用MYC和AKT激活的抑制源凋亡耐药性的程度。 在AIM 2中，我们将在免疫缺陷小鼠中生长的高危人类T-Alls中的生化分析与治疗研究相结合，以识别和克服高危人类T-All中凋亡耐药性的机制。预计此处提出的工作的成功完成将导致鉴定T-All细胞中对化学疗法诱导的凋亡的抗性机制，以及对克服这些策略的发展。鉴于大多数具有高风险T-A​​ll的患者无法使用当前的治疗方案治愈，因此预计新型高风险T-A​​LL的新型有效疗法将代表这些患者的主要治疗疗法。 公共卫生相关性：尽管有所改善，但目前对T细胞急性淋巴细胞白血病（T-All）的治疗仍在20％的儿童和超过50％的成年人中失败，这些患者的预后较差。 高危人类T-ALL与AKT和MYC途径的激活有关，我们已经表明，这些途径阻止了斑马鱼T-ALL细胞中的细胞死亡，这意味着这些途径抗化疗诱导的细胞死亡。 在这里，我们建议将人类和斑马鱼T的研究结合起来，以确定这种封锁细胞死亡的机制，并测试克服这种封锁并诱导高危T-ALL细胞中的细胞死亡的治疗策略。