Arsenic Trioxide Activaed Pathways in APL

描述（由申请人提供）：三氧化二砷（As 2 O3）是一种重金属衍生物，在体外和体内具有强效抗白血病特性。该药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。我们已经确定了APL细胞中三氧化二砷激活的一种新型信号通路，涉及p38 Map激酶。我们的数据表明，该信号级联的激活对APL细胞的凋亡和细胞分化的诱导表现出负调控作用。这项资助申请的总体目标是了解p38负调控APL细胞中AS 2 O3反应诱导的机制。具体目标A是确定APL细胞中As 2 O3激活p38 Map激酶的机制。将进行研究以检查小GTP酶Rac 1和Cdc 42以及Pak 1激酶的作用，并鉴定直接磷酸化和激活p38的Map激酶激酶（Mkk）。具体目标B是鉴定p38 Map激酶控制AS 2 O3依赖性细胞凋亡的下游效应机制。研究提出，以检查不同的p38亚型在APL细胞中的激活模式，并确定其在产生AS 2 O3-反应的作用。还将进行实验，以剖析p38通路的不同下游效应物在调节此类反应中的贡献。具体目标C是检查APL患者或其他亚型急性髓细胞白血病（AML）患者的原发性白血病原始细胞中p38的活化，并确定这种活化是否与对三氧化二砷作用的敏感性或抗性相关。总之，这些研究应该推进我们对As 2 O3对恶性细胞产生影响的机制的全面理解。它们也可能为AS 2 O3和p38抑制剂组合用于治疗APL和可能的其他形式的AML的未来临床转化努力提供基础。

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.