Rac GTPase Inhibition in Chronic Myelogenous Leukemia

描述（由申请方提供）：慢性髓性白血病中的Rac GT3抑制。慢性粒细胞白血病（Chronic myelogenous leukemia，CML）是一种以p210-BCR-ABL融合基因表达失调为特征的克隆性骨髓增生性疾病，P210-BCR-ABL是CML发生和维持的必需基因。p210-BCR-ABL分子靶向抑制ABL激酶活性可抑制CML细胞生长并诱导其凋亡。然而，Abl激酶抑制剂不能根除该疾病，并且需要靶向HSC/P中p210-BCR-ABL下游信号传导的替代方案。由于Rac活性失调与癌症转化有关，（并且我们先前已经显示了Rac 1和Rac 2 Rho GTP酶在调节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，Rac GTP酶同工型在p210-BCR-ABL的启动和/或维持中发挥不同的作用。ABL诱发的白血病通过利用基因靶向小鼠缺乏Rac 1，Rac 2和Rac 3和药理学方法在体外和体内的小鼠和人类疾病，我们已经产生了初步的数据表明，Rac蛋白在白血病的p210-BCR-ABL在体外和体内的作用发挥了重要作用。在特定目标1中，我们将研究Rho GTP酶Rac 1、Rac 2和Rac 3或其组合在白血病起始和细胞转化中的体外和体内需求。我们还将研究Rac效应子和下游信号在白血病起始中的作用。在特异性目的2中，我们将分析Rac（和特异性Rac亚型）在p210-BCR-ABL诱导的白血病维持中是否发挥独特或冗余的作用。最后，我们将分析Rac激活的白血病维持的下游信号是否不同于启动所需的下游信号。本项目的研究结果将验证Rac GTP酶作为CML新分子靶点的潜在作用，并分析Rac激活所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BCR/ABL异常蛋白表达引起的疾病。Rac GTP酶是一组在细胞中起分子开关作用的蛋白质。我们将分析Rac GTP酶是否对BCR/ABL诱导的白血病的发展至关重要，并分析依赖于Rac GTP酶负责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.