Role of RNA Binding Proteins in BCR/ABL Leukemogenesis

RNA 结合蛋白在 BCR/ABL 白血病发生中的作用

• 批准号: 7763885
• 负责人: Danilo Perrotti
• 金额: $ 25.08万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7763885
• 关键词: Affect; Apoptosis; Automobile Driving; Biology; Blast Cell; Blast Phase; Bone Marrow; CCAAT-Enhancer-Binding Proteins; CD34 gene; Cell Line; Cells; Chronic Myeloid Leukemia; Chronic-Phase Myeloid Leukemia; Clinical Trials; Dasatinib; Development; Disease; Disease Progression; Forskolin; Functional disorder; Gene Expression; Goals; Hematopoietic; Imatinib; In Vitro; Investigation; Knowledge; Leukemic Cell; Link; MDM2 gene; Malignant Neoplasms; Marrow; Messenger RNA; Metabolism; MicroRNAs; Modeling; Molecular; Nuclear; Nuclear Export; Oncogenic; Outcome; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Process; Protein Phosphatase 2A Regulatory Subunit PR53; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Protein c-kit; RNA Binding; RNA-Binding Proteins; Regulation; Regulator Genes; Reporting; Research; Resistance; Role; Signal Transduction; Specimen; Staging; Stem cells; Therapeutic Intervention; Translating; Translations; Tumor Suppressor Proteins; Work; activator 1 protein; anticancer research; base; bcr-abl Fusion Proteins; cancer cell; in vivo; kinase inhibitor; leukemia; leukemogenesis; loss of function; mouse model; prevent; progenitor; protein K; protein expression; public health relevance; response; stem; therapeutic target

DESCRIPTION (provided by applicant): Understanding the biology of Chronic Myelogenous Leukemia (CML) disease progression is of critical importance, as the advanced stage of the disease is often associated with a dismal outcome. We extensively reported that altered mRNA metabolism is a key feature of blast crisis CML (CML-BC). Indeed, loss-of-function of tumor suppressors (e.g. PP2A, C/EBPa) and enhanced expression of pro-oncogenic factors (e.g. MYC, MDM2 and BCL-XL) in CML-BC results from aberrant mRNA processing, nuclear export and/or translation. Given that a) BCR/ABL levels are increased in the CML-BC leukemia-initiating cell; b) a causal relationship exists between BCR/ABL levels/activity and altered mRNA metabolism; and c) molecular and/or pharmacologic interference with the expression and/or activity of the RNA binding proteins hnRNP A1, E2 and K antagonizes both in vitro and in vivo BCR/ABL leukemogenesis by impairing proliferation, inhibiting survival and/or restoring differentiation of BCR/ABL+ hematopoietic progenitors; the hypothesis driving this proposal is that BCR/ABL initiates a hierarchical activation of signals leading to a temporally- and developmentally-organized increase in the expression/function of these RNA binding proteins, and that this represents an essential step for disease progression. Based on these considerations, the overall objective is to further understand the importance of altered mRNA metabolism for the pathophysiology of CML-BC through an integrated in vitro and in vivo analysis of the temporal changes in expression/function of the BCR/ABL-regulated hnRNPs and of their interplay/interaction with other post-transcriptional regulators of gene expression (e.g. microRNAs). Specifically, CML-BC specimens, the unique SCL-tTA-BCR/ABL mouse model of disease progression and BCR/ABL+ cell lines will be used to assess whether 1) BCR/ABL-dependent regulation of hnRNP A1, K and E2 expression/activity follows a hierarchical order and at which stage of the CML stem/progenitor cell development it occurs; 2) in vivo modulation of hnRNP A1, E2 and K expression/activity prevents CML blastic transformation; and 3) in vitro and in vivo the role of miR-223 and miR-328 in the regulation of hnRNP E2 translation-modulatory activity in CML-BC. If successful, this investigation will formally establish a functional link between CML progression, BCR/ABL expression and altered mRNA metabolism, and will indicate the incorporation of drugs capable of antagonizing the BCR/ABL-hnRNP-regulated pathways in the therapy of Ph1 leukemias and, perhaps, of other cancers characterized by similar alteration in mRNA metabolism. Note that our discovery of the BCR/ABL-hnRNP A1-SET-PP2A inhibitory pathway and of its importance as a feasible therapeutic target in imatinib/dasatinib-sensitive and -resistant CML-BC and Ph1 ALL is in the process to be translated into clinical trials. Hence, the strong relevance of the proposed studies for basic and translational cancer research. PUBLIC HEALTH RELEVANCE: Understanding the mechanisms underlying CML disease progression is of critical importance, as CML-BC often does not respond to conventional kinase inhibitor therapy and is usually associated with a dismal outcome. If the proposed studies will determine modulation of RNA binding protein expression and function antagonize disease progression and efficiently induce apoptosis in the leukemia-initiating cells, the anti- leukemic effects of drug capable of altering the effects of aberrant hnRNP activity may be assessed in clinical trials. Thus, it is clear that, if successful, the proposed research will have a strong impact on leukemia research and patient care.

描述（由申请人提供）：了解慢性骨髓性白血病（CML）疾病进展的生物学至关重要，因为该疾病的晚期阶段通常与惨淡的结果有关。我们广泛报道了mRNA代谢改变是BLAST危机CML（CML-BC）的关键特征。实际上，在CML-BC中，肿瘤抑制因子（例如PP2A，C/EBPA）的功能丧失（例如PP2A，C/EBPA）和增强的亲源性因子（例如MYC，MDM2和BCL-XL）的表达是由异常的mRNA处理，核Export，核输出和/或翻译而引起的。鉴于A）CML-BC白血病发射细胞中的BCR/ABL水平升高； b）BCR/ABL水平/活性与mRNA代谢改变之间存在因果关系；和c）分子和/或药理学干扰RNA结合蛋白HNRNP A1，E2和K的表达和/或活性会在体外和体内BCR/ABL白血病中拮抗增殖，从而抑制BCR/或恢复BCR/ABL+血小板的分化。推动该建议的假设是，BCR/ABL启动了信号的层次激活，导致这些RNA结合蛋白的表达/功能增加，这是疾病进展的重要步骤。基于这些考虑，总体目标是进一步理解mRNA代谢改变对CML-BC的病理生理的重要性，通过整合的体外和体内分析BCR/ABL调节的HNRNP的表达/功能的时间变化，以及与其他后移植量调节剂的相互作用/相互作用（E.G）。具体而言，CML-BC标本，独特的SCL-TTA-BCR/ABL小鼠疾病进展和BCR/ABL+细胞系模型将用于评估1）1）BCR/ABL依赖性HNRNP A1，K和E2表达/活动的调节是否遵循CML STEM/Progentor Cell expression it CML的阶段，其阶段2）HNRNP A1，E2和K表达/活性的体内调节可防止CML Blastic Transcration； 3）体外和体内miR-223和miR-328在CML-BC中HNRNP E2翻译调节活性调节中的作用。如果成功，这项研究将正式建立CML进展，BCR/ABL表达和改变mRNA代谢之间的功能联系，并将指示能够纳入能够拮抗BCR/ABL-HNRNP调节的途径在PH1白血病治疗中的疗法，以及其他通过类似MRNA METNA METNA METNABOLISM中的Cancers cancers的疗法。请注意，我们发现了BCR/ABL-HNRNP A1-SET-PP2A抑制途径，并且在伊马替尼/dasatinib敏感和耐药的CML-BC中，它是可行的治疗靶标的，并且PH1在此过程中都可以转化为临床试验。因此，拟议的基础癌症研究和转化性癌症研究的强烈相关性。公共卫生相关性：了解CML疾病进展的基础机制至关重要，因为CML-BC通常对传统的激酶抑制剂疗法反应，并且通常与惨淡的结果有关。如果拟议的研究将确定RNA结合蛋白表达的调节并功能拮抗疾病的进展并有效诱导白血病发射细胞中的凋亡，那么在临床试验中，可以评估能够改变异常HNRNP活性作用的药物的抗白血病作用。因此，很明显，如果成功的话，拟议的研究将对白血病研究和患者护理产生重大影响。