CSF2 receptor mediated actions in t(8;21) leukemia
CSF2 受体介导的 t(8;21) 白血病作用
基本信息
- 批准号:9014529
- 负责人:
- 金额:$ 34.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AML1-ETO fusion proteinAcute Myelocytic LeukemiaAddressAffectAgeAllelesApoptosisBlast PhaseCBFA2T1 geneCSF2RA geneCell Cycle ArrestCell LineCell ProliferationCell SurvivalCell modelCellsChimeric ProteinsChromosomal translocationChromosomes, Human, Pair 21Chromosomes, Human, Pair 8Chromosomes, Human, XColony-Stimulating Factor ReceptorsColony-Stimulating FactorsDataDevelopmentDiagnosisEthnic groupFrequenciesFundingGenesGeographic LocationsGoalsHealthHematopoiesisHematopoieticHematopoietic NeoplasmsHumanIL5 geneIncidenceInterleukin-3 ReceptorK-562K562 CellsKnowledgeLeadM2 Acute Myeloid LeukemiaMediatingMolecularMusMyelogenousOutcomePathway interactionsPatientsPlayProductionProteinsPseudoautosomal RegionRUNX1 geneRelapseReportingResistanceRoleSex ChromosomesSignal PathwaySignal TransductionStem cellsTestingTimeToxic effectTransgenic MiceX ChromosomeY Chromosomealternative treatmentautosomebasebcr-abl Fusion Proteinschemotherapycytokineeffective therapyin vitro Assayin vivoinsightinterestleukemialeukemic stem cellleukemogenesismouse modelnovelnovel strategiesoutcome forecastpromoterreceptorself-renewalstandard of carestemt(821)(q22q22)targeted treatment
项目摘要
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 2R 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,重要的是要找到新的方法来在初始诱导治疗期间消除t(8; 21)白血病干细胞并阻止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AML1基因的融合导致AML1-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 2R 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 2R 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AML1-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 2RA表达对t(8; 21)白血病发生的影响。拟议的研究基于我们积累的知识和最近的新发现,涉及AML 1-ETO诱导的白血病中的CSF 2信号传导和CSF 2 R α。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。
项目成果
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{{ truncateString('DONG-ER ZHANG', 18)}}的其他基金
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 - 财政年份:2015
- 资助金额:
$ 34.49万 - 项目类别:
Synergestic roles of SRF2 and RUNX1 in blood cell development and pathology
SRF2 和 RUNX1 在血细胞发育和病理学中的协同作用
- 批准号:
10400021 - 财政年份:2013
- 资助金额:
$ 34.49万 - 项目类别:
ISG15 and protein ISGylation in Cancer
癌症中的 ISG15 和蛋白质 ISGylation
- 批准号:
8616739 - 财政年份:2013
- 资助金额:
$ 34.49万 - 项目类别:
Synergestic roles of SRF2 and RUNX1 in blood cell development and pathology
SRF2 和 RUNX1 在血细胞发育和病理学中的协同作用
- 批准号:
9922899 - 财政年份:2013
- 资助金额:
$ 34.49万 - 项目类别:
ISG15 and protein ISGylation in Cancer
癌症中的 ISG15 和蛋白质 ISGylation
- 批准号:
8535417 - 财政年份:2013
- 资助金额:
$ 34.49万 - 项目类别:
ISG15 and Protein ISGylation in Cancer
癌症中的 ISG15 和蛋白质 ISG 化
- 批准号:
10116297 - 财政年份:2013
- 资助金额:
$ 34.49万 - 项目类别:
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