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: 8842430
• 负责人: DONG-ER ZHANG
• 金额: $ 34.59万
• 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/8842430
• 关键词: AML1-ETO fusion protein; Acute Myelocytic Leukemia; Address; Affect; Age; Alleles; Apoptosis; Blast Phase; 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; 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; public health relevance; 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）：该提案的总体目标是了解 CSF2 及其特异性受体 CSF2Rα 在 t(8;21) 白血病发展中的作用 8 号和 21 号染色体易位，t(8;21)。 (q22;q22)，导致 40% 的 FAB M2 型急性髓系白血病 (AML) 的发生，据报道8-15% 的 AML 病例，具体取决于地理位置和种族群体。大多数 AML 患者在初次诊断时年龄超过 60 岁。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，但5年内的累积复发率为47%，中位总生存时间仅为47%。在新发 t(8;21) AML 患者中，治疗相关的 t(8;21) AML 没有良好的结果，因此，确定消除 t(8;21) AML 的新方法非常重要。 8号染色体上的ETO基因与21号染色体上的AML1基因在t(8;21)中的融合导致了白血病干细胞在初始诱导治疗期间的存活和增殖。使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) 负向调节 AML1-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 CSF2 特异性受体亚基 CSF2Rα 的表达会降低细胞增殖和存活。在本次资助申请中，我们将测试所选的假设。 CSF2 下游通路在抑制 t(8;21) 白血病中发挥关键作用，并且 CSF2Rα 在抑制 t(8;21) 白血病中可能具有独立于 CSF2 信号传导的功能，我们建议进行以下研究来检验假设：具体目标 1，我们将表征 CSF2 信号传导介导抑制 AML1-ETO 诱导的白血病的分子途径；在具体目标 2，我们将分析 CSF2RA 表达对 AML1-ETO 诱导白血病的影响； t(8;21) 白血病发生。拟议的研究基于我们积累的知识和最近涉及 AML1-ETO 诱导的白血病中 CSF2 信号传导和 CSF2Rα 的新发现，我们的提案将共同解决造血和白血病发生中尚未解答的重要问题。为 t(8;21) 白血病的治疗提供有价值的见解。