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

CSF2 受体介导的 t(8;21) 白血病作用

• 批准号: 9014529
• 负责人: DONG-ER ZHANG
• 金额: $ 34.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-13 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014529
• 关键词: AML1-ETO fusion protein; Acute Myelocytic Leukemia; Address; Affect; Age; Alleles; Apoptosis; Blast Phase; CBFA2T1 gene; CSF2RA gene; Cell Cycle Arrest; Cell Line; Cell Proliferation; Cell Survival; Cell model; Cells; Chimeric Proteins; Chromosomal translocation; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Chromosomes, Human, X; Colony-Stimulating Factor Receptors; Colony-Stimulating Factors; Data; Development; Diagnosis; Ethnic group; Frequencies; Funding; Genes; Geographic Locations; Goals; Health; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Human; IL5 gene; Incidence; Interleukin-3 Receptor; K-562; K562 Cells; Knowledge; Lead; M2 Acute Myeloid Leukemia; Mediating; Molecular; Mus; Myelogenous; Outcome; Pathway interactions; Patients; Play; Production; Proteins; Pseudoautosomal Region; RUNX1 gene; Relapse; Reporting; Resistance; Role; Sex Chromosomes; Signal Pathway; Signal Transduction; Stem cells; Testing; Time; Toxic effect; Transgenic Mice; X Chromosome; Y Chromosome; alternative treatment; autosome; base; bcr-abl Fusion Proteins; chemotherapy; cytokine; effective therapy; in vitro Assay; in vivo; insight; interest; leukemia; leukemic stem cell; leukemogenesis; mouse model; novel; novel strategies; outcome forecast; promoter; receptor; self-renewal; standard of care; stem; t(8; 21)(q22; q22); targeted treatment

 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.

 描述（由申请人提供）：本提案的总体目标是了解CSF 2及其特异性受体CSF 2 R α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FAB M2型急性髓性白血病（AML）的发生，并且在8-15%的AML病例中报告，这取决于地理位置和种族群体。年龄是AML最相关的因素。大多数AML患者在初次诊断时年龄超过60岁。然而，t（8;21）AML患者相对年轻，大多数对初始化疗反应良好。因此，t（8;21）AML通常被认为预后良好。然而，5年内复发的累积发生率为47%，初治t（8;21）AML患者的中位总生存时间仅为5年。此外，治疗相关的t（8;21）AML没有有利的结局。因此，重要的是要确定新的方法来消除t（8;21）白血病干细胞在初始诱导治疗和阻断化疗耐药白血病细胞的生存和增殖。t（8;21）中8号染色体ETO基因与21号染色体AML 1基因的融合导致AML 1-ETO异常蛋白的表达。使用几种转基因小鼠模型和可用的人类患者数据，我们发现集落刺激因子2（CSF 2）负调控AML 1-ETO诱导的造血干/祖细胞自我更新和AML发展。此外，t（8;21）AML细胞中CSF 2特异性受体亚基CSF 2 R α的表达降低了细胞增殖和存活。在本基金申请中，我们将测试以下假设：选定的CSF 2下游通路在抑制t（8;21）白血病中起关键作用，CSF 2 R α在抑制t（8;21）白血病中可能具有独立于CSF 2信号传导的功能。我们建议进行以下研究来验证假设：在具体目标1中，我们将表征介导AML 1-ETO诱导的白血病抑制的CSF 2信号传导的分子途径;在具体目标2中，我们将分析CSF 2 RA表达对t（8;21）白血病发生的影响。这些研究是基于我们对AML 1-ETO诱导的白血病中CSF 2信号转导和CSF 2 R α的积累和最新发现。总的来说，我们的建议将解决造血和白血病发生中重要的未回答的问题，旨在为t（8;21）白血病的治疗提供有价值的见解。