Arsenic Trioxide activated pathways in malignant cells

描述(由申请人提供)：这是一项竞争性的续展申请，其总体目标是确定三氧化二砷(As2O3)抗白血病作用的产生机制，并开发增强其抗肿瘤特性的手段和方法。三氧化二砷是一种重金属衍生物，在体内外具有很强的抗白血病活性，对急性早幼粒细胞白血病(APL)患者具有高效的治疗作用。尽管该领域取得了进展，人们对将砷的使用扩展到其他血液系统恶性肿瘤也很感兴趣，但As_2O_3诱导抗白血病反应的确切机制尚不清楚。我们提供了第一个证据，表明As2O3诱导的自噬对于其对髓系白血病患者原始白血病祖细胞的抑制作用是必不可少的。目前的建议是一种系统的方法，以确定导致As_2O_3依赖的自噬的细胞事件，并确定自噬介导原始白血病前体细胞和白血病起始干细胞(LIC)中致癌蛋白降解的机制。特指目标1将研究三氧化二砷在白血病祖细胞中自噬的机制。将进行研究，以确定白血病细胞自噬级联中的上游激酶，并确定导致它们对砷的响应而激活的事件序列。其他研究将检查自噬与细胞负反馈调节通路(NFRP)的关系，NFRP是对As2O3的反应诱导的。具体目标2将确定自噬介导原始祖细胞和白血病启动干细胞对急性髓细胞白血病和慢性粒细胞白血病患者的砷反应的效应机制。将进行实验，以确定自噬是否介导了不同癌蛋白依赖砷的降解，并确定了发生这种情况的确切机制。其他研究将确定自噬机制元件的药理学或分子靶向性是否可以增强砷诱导的对原始白血病前体和LICs的抑制。特定目的3将在体内不同的白血病小鼠模型中检测自噬在砷依赖的抗白血病反应中的作用。它包括实验，以确定是否需要自噬在体内的抗白血病特性，并检查是否其他自噬诱导剂显示协同抗白血病活性与三氧化二砷。总之，这项工作将促进我们对As2O3产生抗白血病反应的机制的理解。它应该具有重要的临床翻译意义，并可能导致开发新的方法，利用三氧化二砷和其他自噬诱导剂的组合来靶向早期祖细胞和LIC。

DESCRIPTION (provided by applicant): This is a competing renewal application whose overall objective is to define the mechanisms of generation of the antileukemic effects of arsenic trioxide (As2O3) and to develop means and ways to enhance its antitumor properties. As2O3 is a heavy metal derivative with potent antileukemic activities in vitro and in vivo and it is highly effective in the treatment of patients with acute promyelocytic leukemia (APL). Despite advances in the field and the high interest to expand the use of arsenic to other hematological malignancies, the precise mechanisms by which As2O3 induces antileukemic responses are not known. We have provided the first evidence that As2O3 -induced autophagy is essential for generation of its suppressive effects on primitive leukemic progenitors from patients with myeloid leukemias. The current proposal is a systematic approach to define the cellular events that lead to As2O3 -dependent autophagy and to identify the mechanisms of autophagy-mediated degradation of oncogenic proteins in primitive leukemic precursors and leukemia initiating stem cells (LICs). Specific aim 1 will examine the mechanisms of As2O3 -autophagy in leukemic progenitor cells. Studies will be performed to identify upstream kinases in the autophagic cascade in leukemia cells and to define the sequence of events leading to their activation in response to arsenic. Other studies will examine the relationship of autophagy with cellular negative feedback regulatory pathways (NFRPs) that are induced in response to As2O3. Specific aim 2 will identify effector mechanisms by which autophagy mediates arsenic- responses on primitive progenitors and leukemia initiating stem cells from patients with AML and CML. Experiments will be performed to define whether autophagy mediates arsenic-dependent degradation of different oncoproteins and to define the precise mechanisms by which this occurs. Other studies will determine whether pharmacological or molecular targeting of elements of the autophagic machinery can enhance arsenic-induced suppression of primitive leukemic precursors and LICs. Specific aim 3 will examine the role of autophagy in arsenic-dependent antileukemic responses in different leukemia mouse models in vivo. It involves experiments to determine whether autophagy is required for the antileukemic properties of As2O3 in vivo and to examine whether other inducers of autophagy exhibit synergistic antileukemic activities with As2O3. Altogether, this work will advance our understanding of the mechanisms by which As2O3 generates antileukemic responses. It should have important clinical-translational implications and possibly lead to the development of novel approaches to target early progenitors and LICs using combinations of As2O3 with other autophagy inducers.