Mitochondrial Apoptotic Sensitivity in Predicting Acute Myeloid Leukemia Response

描述（由申请人提供）：成人急性髓性白血病是一种癌症，具有非常高的初始治疗成功率，但许多患者由于复发而长期失败。一种解释是，耐药亚群可能在初始治疗中存活，以重新建立癌症。已经观察到，对化疗的抗性与由BCL-2家族成员之间的相互作用决定的凋亡敏感性相关。特别地，我们已经在细胞系中发现，线粒体对模拟Bcl-2同源3（BH 3）结构域的肽形式的凋亡信号的敏感性降低与细胞对化疗的敏感性降低相关。为了测量复杂、异质性原发性AML样本中单个细胞的线粒体敏感性，我们基于这些肽反应开发了一种基于FACS的BH 3谱分析技术。该提案旨在测试BH 3谱是否可以作为患者结果的预后预测因子，检测耐药子集并鉴定可能的BCL-2家族抗凋亡成员，其可以靶向选择性杀死AML细胞，但不杀死重要的正常造血祖细胞。此外，由于BH 3肽通过抑制某些抗凋亡BCL-2家族成员而特异性杀伤，因此某些肽的杀伤效果可以显示哪些BCL-2成员将是未来药物靶向的良好候选者。 公共卫生相关性：目前的研究表明，癌症由具有潜在不同药物敏感性的恶性细胞混合物组成。最重要的是，CD 34？据称，急性髓性白血病（AML）祖细胞亚群在药物治疗后存活并导致癌症复发。该项目评估了每个AML细胞如何在化疗药物引发的死亡线索中存活，并可能为杀死耐药人群开辟途径。

DESCRIPTION (provided by applicant): Adult acute myeloid leukemia is a type of cancer that exhibits a remarkably high initial treatment success rate yet many patients fail long-term due to relapse. One explanation is that a drug resistant subset may survive initial treatment to re-establish the cancer. It has been observed that resistance to chemotherapy correlates with apoptotic sensitivity determined by the interactions among the BCL-2 family members at the mitochondrion. Particularly, we have found in cell lines that diminished mitochondrial sensitivity to apoptotic signals in the form of peptides mimicking the Bcl-2 homology 3 (BH3) domains correlates with decreased cellular sensitivity to chemotherapy. To measure the mitochondrial sensitivity of individual cells in complex, heterogeneous primary AML samples, we have developed a FACS-based BH3 profiling technique based on these peptide responses. This proposal aims to test if BH3 profiling can serve as a prognostic predictor of patient outcome, detect resistant subsets and identify possible BCL-2 family anti-apoptotic members that can be targeted to selectively kill AML cells but not important normal hematopoietic progenitors. Furthermore, since the BH3 peptides specifically kill by inhibiting certain anti-apoptotic BCL-2 family members, the effectiveness of killing by certain peptides can show which BCL-2 members would be good candidates for future drug targeting. PUBLIC HEALTH RELEVANCE: Current research suggests that cancer consists of a mixture of malignant cells with potentially different drug sensitivity. Most significantly, the CD34? subset of progenitor acute myeloid leukemia (AML) cells are purported to survive drug treatment and contribute to cancer relapse. This project assesses how each AML cell survives death cues triggered by the presence of chemotherapeutic drugs and may open avenues for killing the resistant population.