Mitochondrial Apoptotic Sensitivity in Predicting Acute Myeloid Leukemia Response

描述(申请人提供)：成人急性髓系白血病是一种癌症，其初期治疗成功率非常高，但许多患者由于复发而长期失败。一种解释是，耐药亚群可能在最初的治疗中存活下来，以重建癌症。已经观察到，对化疗的抵抗与细胞凋亡的敏感性有关，这种敏感性由线粒体上bcl2家族成员之间的相互作用决定。特别是，我们发现在细胞系中，线粒体对凋亡信号的敏感性降低，其形式类似于BH3(BH3)结构域，与细胞对化疗的敏感性降低有关。为了测量复杂、异质的原发AML样本中单个细胞的线粒体敏感性，我们开发了一种基于这些肽反应的基于FACS的BH3图谱技术。这项建议旨在测试BH3图谱是否可以作为患者预后的预测指标，检测耐药亚群，并识别可能的bcl2家族抗凋亡成员，这些成员可以选择性地杀伤AML细胞，但不能选择性地杀死重要的正常造血祖细胞。此外，由于BH3多肽通过抑制某些抗凋亡的bcl2家族成员而特异性地杀伤，因此某些多肽的杀伤效果可以表明哪些bcl2成员将成为未来药物靶向的良好候选者。 与公共卫生相关：目前的研究表明，癌症是由具有潜在不同药物敏感性的恶性细胞组成的混合物。最重要的是，CD34？急性髓系白血病(AML)祖细胞亚群被认为在药物治疗中存活下来，并有助于癌症复发。该项目评估每个AML细胞如何在化疗药物的存在引发的死亡信号中幸存下来，并可能开辟杀死耐药人群的途径。

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.