CSF2 receptor mediated actions in t(8;21) leukemia

 描述(由申请人提供)：本方案的总体目标是了解csf2及其特异性受体csf2Rα在t(8；21)白血病发生中的作用。8号和21号染色体易位t(8；21)(q22；q22)导致40%的FABM2型急性髓系白血病(AML)的发生，根据地理位置和种族的不同，在8%-15%的AML病例中有报道。年龄是急性髓系白血病最相关的因素。大多数AML患者初诊时年龄都在60岁以上。然而，t(8；21)AML患者相对年轻，大多数对初始化疗有良好的疗效。因此，人们普遍认为t(8；21)AML预后良好。然而，初治AML患者5年内累计复发率为47%，中位总生存期仅为5年。此外，与治疗相关的t(8；21)AML没有良好的结果。因此，寻找新的方法在最初的诱导治疗中消除t(8；21)白血病干细胞并阻断耐药白血病细胞的生存和增殖是很重要的。8号染色体上的ETO基因和21号染色体上的AML1基因融合导致异常的AML1-ETO蛋白的表达。利用几种转基因小鼠模型和现有的人类患者数据，我们发现集落刺激因子2(CSF2)对AML1-ETO诱导的造血干/祖细胞的自我更新和AML的发展具有负性调节作用。此外，csf2特异性受体亚单位csf2Rα在t(8；21)急性髓系白血病细胞中的表达降低了细胞的增殖和存活。在这项资金申请中，我们将检验假设，即选择的CSF2下游通路在抑制t(8；21)白血病中发挥关键作用，以及CSF2Rα可能具有不依赖于CSF2信号的抑制t(8；21)白血病的功能。我们建议进行以下研究来验证假设：在特定目标1中，我们将表征CSF2信号转导抑制AML1-ETO诱导的白血病的分子途径；在特定目标2中，我们将分析CSF2RA表达在t(8；21)白血病发生中的作用。建议的研究是基于我们积累的知识和最近关于AML1-ETO诱导的白血病中CSF2信号和CSF2Rα的新发现。总而言之，我们的建议将解决造血和白血病发生中尚未回答的重要问题，旨在为t(8；21)白血病的治疗提供有价值的见解。

 DESCRIPTION (provided by applicant): The overall goal of this proposal is to understand the role of CSF2 and its specific receptor CSF2Rα in the development of t(8;21) leukemia. The 8 and 21 chromosome translocation, t(8;21)(q22;q22), is responsible for the development of 40% of FAB M2 type of acute myeloid leukemia (AML) and is reported in 8-15% of cases of AML, depending on geographic locations and ethnic groups. Age is the most correlated factor for AML. Most AML patients are over 60 years old at the initial diagnosis. However, t(8;21) AML patients are relatively young and most respond to initial chemotherapy well. Therefore, t(8;21) AML is generally considered with favorable prognosis. However, the cumulative incidence of relapse in 5 years is 47%, and the median overall survival time is only 5 years among de novo t(8;21) AML patients. Furthermore, therapy-related t(8;21) AML does not have a favorable outcome. Therefore, it is important to identify new approaches to eliminate t(8;21) leukemia stem cells during the initial induction treatment and to block the survival and proliferation of chemo-resistant leukemia cells. The fusion of ETO gene on chromosome 8 and AML1 gene on chromosome 21 in t(8;21) leads to the expression of the abnormal AML1-ETO protein. Using several transgenic mouse models and available human patient data, we discovered that colony stimulating factor 2 (CSF2) negatively regulates AML1-ETO induced self-renewal of hematopoietic stem/progenitor cells and AML development. Furthermore, expression of the CSF2-specific receptor subunit, CSF2Rα, in t(8;21) AML cells reduces cell proliferation and survival. In this funding application, we will test the hypotheses that selected CSF2 downstream pathways play critical roles in suppression of t(8;21) leukemia and that CSF2Rα may have functions independent of CSF2 signaling in inhibition of t(8;21) leukemia. We propose to perform the following studies to test the hypotheses: in specific aim 1, we will characterize the molecular pathways of CSF2 signaling that mediate inhibition of AML1-ETO induced leukemia; in specific aim 2, we will analyze the effect of CSF2RA expression on t(8;21) leukemogenesis. The proposed studies are based on our accumulated knowledge and recent novel findings involving CSF2 signaling and CSF2Rα in AML1-ETO induced leukemia. Collectively, our proposal will address important unanswered questions in hematopoiesis and leukemogenesis, which aim to provide valuable insight into the treatment of t(8;21) leukemia.