Rac GTPase Inhibition in Chronic Myelogenous Leukemia

描述(申请人提供)：慢性粒细胞白血病的RAC GTP酶抑制。慢性粒细胞白血病(CML)是一种融合基因p210-bcr-abl表达失控的克隆性骨髓增生性疾病。启动和维持慢性粒细胞白血病需要P210-BCR-ABL。P210-bcr-abl通过抑制ABL激酶活性的分子靶向，抑制CML细胞的生长并诱导其凋亡。然而，Abl激酶抑制剂不能根除这种疾病，需要针对HSC/P中p210-bcr-abl下游信号的替代药物。由于Rac活性异常与肿瘤转化有关(我们之前已经证明了rac1和rac2 Rho GTPase在调节HSC/P的增殖、干细胞定位和凋亡中的作用)，我们假设完整的p210-bcr-abl介导的造血干细胞转化需要Rac活性，并且Rac GTPase亚型在p210-bcr-abl诱导的白血病的启动和/或维持中起着不同的作用。通过利用缺乏rac1、rac2和rac3的基因靶向小鼠以及在小鼠和人类疾病中的体外和体内药理学方法，我们已经产生了初步的数据，表明Rac蛋白在p210-bcr-abl的体外和体内的白血病作用中发挥着重要的作用。在特定的目标1中，我们将研究Rho GTP酶rac1、rac2和rac3及其组合在体外和体内对白血病启动和细胞转化的需求。我们还将研究RAC效应器和下游信号在白血病启动中的作用。在特定的目标2中，我们将分析RAC(和特定的RAC亚型)在p210-bcr-abl诱导的白血病的维持中是否起着明显或多余的作用。最后，我们将分析RAC激活的白血病维持下游信号是否与启动所需的信号不同。该项目的结果将验证Rac GTP酶作为CML新的分子靶点的潜在作用，并剖析Rac激活诱导的白血病发生所需的信号和潜在的白血病治疗新靶点。公共卫生相关性：慢性粒细胞白血病是一种由一种名为bcr/abl的异常蛋白表达引起的疾病。Rac GTP酶是一组蛋白质，在细胞中扮演分子开关的角色。我们将分析Rac GTP酶是否在bcr/abl诱导的白血病的发生中起关键作用，并分析依赖于Rac GTP酶导致白血病形成的具体机制。

DESCRIPTION (provided by applicant): Rac GTPase inhibition in Chronic Myelogenous Leukemia. Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease with deregulated expression of the fusion gene p210-BCR-ABL. P210-BCR-ABL is needed to initiate and maintain CML. Molecular targeting of p210-BCR-ABL by inhibiting the abl kinase activity can suppress growth and induces apoptosis of CML cells. However, Abl kinase inhibitors are not able to eradicate the disease and alternatives targeting signaling downstream of p210-BCR-ABL in HSC/P are required. Since dysregulated Rac activity has been implicated in cancer transformation (and we have previously shown the role of Rac1 and Rac2 Rho GTPases in regulating proliferation, stem cell localization and apoptosis of HSC/P), we hypothesize that full p210-BCR-ABL mediated transformation of hematopoietic stem cells requires Rac activity and that Rac GTPase isoforms play distinct roles in the initiation and/or maintenance of p210-BCR- ABL-induced leukemia. By taking advantage of gene-targeted mice lacking Rac1, Rac2 and Rac3 and a pharmacological approach in vitro and in vivo in murine and human disease, we have generated preliminary data to indicate that Rac proteins play an essential role in the leukemogenic effects of p210-BCR-ABL in vitro and in vivo. In Specific Aim 1, we will investigate the requirement of the Rho GTPases Rac1, Rac2 and Rac3, or combinations in vitro and in vivo in leukemia initiation and in cell transformation. We will also investigate the role of Rac effectors and downstream signals in leukemia initiation. In Specific Aim 2, we will analyze whether Rac (and specific Rac isoforms) play distinct or redundant roles in the maintenance of leukeminas induced by p210-BCR-ABL. Finally, we will analyze whether the downstream signals activated by Rac for leukemic maintenance are different from the ones required for initiation. The results obtained from this project will validate the potential role of Rac GTPases as novel molecular targets for CML and dissect out the signals induced by Rac activation required for leukemogenesis and potential new targets for leukemic therapy. PUBLIC HEALTH RELEVANCE: Chronic myelogenous leukemia is a disease caused by the expression of an abnormal protein called BCR/ABL. Rac GTPases are a group of proteins that act as molecular switches in the cells. We will analyze whether Rac GTPases are critical for the development of leukemias induced by BCR/ABL and analyze the specific mechanisms depending on Rac GTPases responsible for leukemia formation.