Arsenic Trioxide Activaed Pathways in APL

描述（由申请人提供）：三氧化二砷（AS2O3）是一种重金属衍生物，在体外和体内具有有效的抗白血病特性。该药物用于治疗急性早幼粒细胞白血病（APL）患者，但其诱导抗白血病作用的确切机制尚不清楚。我们在APL细胞中发现了一种新的由三氧化二砷激活的信号通路，涉及p38 Map激酶。我们的数据表明，该信号级联的激活对APL细胞凋亡和细胞分化的诱导具有负调控作用。这项拨款申请的总体目标是了解p38负调控APL细胞诱导as2o3反应的机制。具体目的A是确定AS2O3在APL细胞中激活p38 Map激酶的机制。研究将检查小gtpase Rac1和Cdc42以及Pak1激酶的作用，并确定直接磷酸化和激活p38的Map激酶（Mkk）。具体目的B是确定p38 Map激酶控制as2o3依赖性细胞凋亡的下游效应机制。研究人员建议研究APL细胞中不同p38-异构体的激活模式，并确定它们在as2o3反应产生中的作用。实验还将进行剖析p38途径的不同下游效应物在这些反应的调节中的贡献。具体目的C是检测APL患者或其他急性髓系白血病（AML）亚型患者原发性白血病母细胞中p38的激活，并确定这种激活是否与对三氧化二砷影响的敏感性或抗性相关。总之，这些研究应该促进我们对AS2O3对恶性细胞产生作用的机制的全面理解。它们也可能为未来AS2O3和p38抑制剂联合治疗APL以及其他形式的AML的临床转化工作提供基础。

DESCRIPTION (provided by applicant): Arsenic trioxide (AS2O3) is a heavy metal derivative that has potent antileukemic properties in vitro and in vivo. This agent is used in the treatment of patients with acute promyelocytic leukemia (APL), but the precise mechanisms by which it induces its antileukemic effects are not known. We have identified a novel signaling pathway activated by arsenic trioxide in APL cells, involving the p38 Map kinase. Our data suggest that activation of this signaling cascade exhibits a negative regulatory role on the induction of apoptosis and cell differentiation of APL cells. The overall goal of this grant application is to understand the mechanisms by which p38 negatively regulates the induction of AS2O3-responses in APL cells. Specific aim A is to determine the mechanisms of activation of the p38 Map kinase by AS2O3 in APL cells. Studies will be performed to examine the roles of the small GTPases Rac1 and Cdc42, and the Pak1 kinase, and to identify the Map kinase kinase (Mkk) that directly phosphorylates and activates p38. Specific aim B is to identify the downstream effector mechanisms by which the p38 Map kinase controls AS2O3-dependent apoptosis. Studies are proposed to examine the patterns of activation of different p38-isoforms in APL cells and to determine their roles in the generation of AS2O3-responses. Experiments will be also performed to dissect the contributions of different downstream effectors of the p38 pathway in the regulation of such responses. Specific aim C is to examine the activation of p38 in primary leukemic blasts from APL patients or patients with other subtypes of acute myeloid leukemia (AML), and determine whether such activation correlates with sensitivity or resistance to the effects of arsenic trioxide. Altogether, these studies should advance our overall understanding of the mechanisms by which AS2O3 generates its effects on malignant cells. They may also provide the basis for future clinical-translational efforts of combinations of AS2O3 and p38 inhibitors for the treatment of APL, and possibly other forms of AML.