Role of p27 in chronic myeloid leukemia and its potential as a therapeutic target

p27 在慢性粒细胞白血病中的作用及其作为治疗靶点的潜力

基本信息

批准号：
8882294
负责人：
Anupriya Agarwal
金额：
$ 24.86万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8882294
关键词：
Adhesions Affect Attenuated Award Biological Assay Bone Marrow Cells Brain CD34 gene Cancer Biology Cell Cycle Cell Cycle Progression Cell Nucleus Cell Proliferation Cells Chronic Myeloid Leukemia Clinical Complex Cyclin-Dependent Kinases Cytoplasm Data Defect Disease Disease Resistance Down-Regulation Drug resistance Environment Extramural Activities Faculty Funding Future Goals Guanosine Triphosphate Phosphohydrolases Health Sciences Hematopoietic Neoplasms Hematopoietic stem cells Human Imatinib Immunoblotting Immunofluorescence Immunologic In Vitro Institutes Knowledge Laboratories Lead Leadership Link Malignant Neoplasms Mediating Mentors Modeling Molecular Molecular Target Molecular and Cellular Biology Mus Nuclear Oncogenes Oncogenic Oregon Outcome Pathogenesis Pathway interactions Patients Philadelphia Chromosome Phosphotransferases Physiological Postdoctoral Fellow Process Prognostic Marker Protein Tyrosine Kinase Reciprocal Translocation Recurrence Research Research Infrastructure Research Personnel Research Training Residual Tumors Resistance Role S Phase SKP2 gene Signal Transduction Skp2 Proteins Solid Staging Stem cells Students Techniques Testing Therapeutic Intervention Training Training Programs Transcript Transgenic Mice Transgenic Organisms Tumor Suppressor Proteins Tyrosine Kinase Inhibitor Universities Up-Regulation Work advanced disease anticancer research attenuation base bcr-abl Fusion Proteins career design drug relapse experience human migration improved in vivo inhibitor/antagonist leukemia leukemogenesis metaplastic cell transformation migration mouse model mutant novel novel strategies outcome forecast progenitor response small molecule therapeutic target tool treatment strategy tyrosine kinase ABL1 ubiquitin ligase

项目摘要

PROJECT SUMMARY/ABSTRACT Career goals: Dr. Agarwal's long term goal is to elucidate novel molecular mechanisms in leukemia pathogenesis so that this knowledge can be applied to the discovery of new therapies resulting in improved clinical outcomes. Dr. Agarwal's career goal is to establish an independent laboratory focused on understanding cancer pathogenesis. For the K99 Pathway to Independence Award, Dr. Agarwal has described a five-year training program that will allow her to acquire the expertise needed to become a successful independent cancer researcher. During this award, she will be able to expand her knowledge in cancer biology, acquire expertise in a variety of novel techniques to be used in her future research, and generate a body of data as a basis for future studies and applications for extramural funding. Knowledge acquired and data produced during the K99/R00 award will be instrumental in achieving her long term goal. Environment: The Oregon Health & Science University Knight Cancer Institute has 165 primary faculty investigators with expertise across a diverse spectrum of fields. Dr. Agarwal's mentor, Dr. Brain Druker, is the Director of the Knight Cancer Institute. Dr. Druker has over 20 years of experience in the field of cancer research and has mentored numerous students and fellows to independent investigator status. He will continue to provide intellectual and leadership training to Dr. Agarwal for the transition to a career as an independent researcher. Dr. Agarwal has gathered an excellent team of collaborators and advisors with the combined expertise to advise her on all aspects of the proposed study as well as on her career. In addition, the Knight Cancer Institute's infrastructure provides research training and enthusiastic support to post-doctoral fellows who are preparing themselves for a successful faculty career. Dr. Agarwal believes that the proposed project is well-suited to launch her independent research career in the field of leukemia pathogenesis. Research: The objective of the proposed study is to determine the mechanism of p27 deregulation in chronic myeloid leukemia (CML) and to establish the role of p27 in CML pathogenesis. CML is a disease of hematopoietic stem cells caused by BCR-ABL, a constitutively active tyrosine kinase that is the result of the 9;22 translocation. Most patients with early stage disease achieve durable responses upon treatment with imatinib, a small-molecule inhibitor of BCR-ABL. However, in the advanced stages of disease, drug resistance and relapse are frequent. Further, recurrence of active disease is common if therapy is stopped. Therefore identification of additional molecular targets suitable for therapeutic intervention may allow us to develop novel treatment strategies designed to overcome disease resistance and eradicate residual disease. Earlier studies showed that BCR-ABL promotes unregulated cell cycle progression and cell proliferation by impairing the function of p27, a tumor suppressor and a regulator of cyclin dependent kinase. However, the detailed mechanism of p27 deregulation remains to be clearly defined. Dr. Agarwal's preliminary data suggests that, in primary CML cells, p27 deregulation involves both downregulation in the nucleus and increased cytoplasmic mislocalization. While nuclear p27 appears to be under the control of BCR-ABL kinase activity, imatinib fails to decrease cytoplasmic p27 levels, suggesting that this process is regulated in a kinase-independent fashion. The low nuclear-to-cytoplasmic p27 ratio in CML progenitors is reminiscent of findings in several types of solid cancers, where such ratios are associated with a poor prognosis. Dr. Agarwal proposes that increased cytoplasmic p27 levels contribute to BCR-ABL- mediated leukemogenesis in CML. In support of this, Dr. Agarwal shows that lack of p27 decreases disease latency in a murine CML model, while experimentally reducing cytoplasmic p27 levels with forced nuclear localization of p27 prolongs survival of leukemic mice. These findings are consistent with a tumor suppressor function of nuclear p27 and a concomitant oncogenic function of cytoplasmic p27. These results also suggest that restoring nuclear p27 expression and reducing cytoplasmic expression may counteract BCR-ABL-induced cellular transformation. In total, Dr. Agarwal's preliminary findings have led to a hypothesis in which BCR-ABL disrupts p27 function by simultaneously inhibiting its nuclear tumor suppressor function and promoting its cytoplasmic oncogenic function. This hypothesis will be tested by three carefully designed specific aims that utilize both in vitro and in vivo approaches: 1) Dr. Agarwal will apply molecular and cellular biology tools to determine the mechanisms by which BCR-ABL upregulates cytoplasmic p27. 2) She will dissect the role of nuclear and cytoplasmic p27 for BCR-ABL-driven leukemogenesis using p27 transgenic murine leukemia models. 3) She will delineate the signaling mechanism(s) by which cytoplasmic p27 mediates cellular transformation of human CML cells by testing the effect of cytoplasmic p27 on invasion and survival pathways. Dr. Agarwal's work will lead to an improved understanding of the role of p27 in CML pathogenesis and provide a platform for developing new approaches to treat CML. Since disruption of physiological p27 function is a common theme in human cancers, findings from this study may have implications beyond CML.

项目概要/摘要职业目标：Agarwal 博士的长期目标是阐明白血病的新分子机制发病机制，以便这些知识可以应用于新疗法的发现，从而改善临床结果。 Agarwal博士的职业目标是建立一个独立的实验室，专注于了解癌症发病机制。对于 K99 独立之路奖，Agarwal 博士描述了为期五年的培训计划将使她能够获得成为成功人士所需的专业知识独立癌症研究员。在获奖期间，她将能够扩展她在癌症生物学方面的知识，获得各种新技术的专业知识以用于她未来的研究，并产生一系列数据作为未来研究和申请外部资金的基础。获取的知识和数据 K99/R00 奖期间制作的作品将有助于实现她的长期目标。环境：俄勒冈健康与科学大学奈特癌症研究所拥有 165 名主要教职人员具有不同领域专业知识的研究人员。阿加瓦尔博士的导师 Brain Druker 博士是奈特癌症研究所所长。 Druker博士在癌症领域拥有20多年的经验研究并指导许多学生和研究员获得独立研究者的地位。他将继续为阿加瓦尔博士提供智力和领导力培训，以过渡到独立职业生涯研究员。阿加瓦尔博士聚集了一支优秀的合作者和顾问团队，专业知识可以就拟议研究的各个方面以及她的职业生涯向她提供建议。此外，骑士癌症研究所的基础设施为博士后研究员提供研究培训和热情支持他们正在为成功的教师生涯做准备。 Agarwal 博士认为，拟议的项目是非常适合在白血病发病机制领域开展她的独立研究生涯。研究：本研究的目的是确定慢性病中 p27 失调的机制。髓性白血病 (CML) 并确定 p27 在 CML 发病机制中的作用。 CML 是一种由 BCR-ABL 引起的造血干细胞疾病，BCR-ABL 是一种持续活跃的酪氨酸激酶，是9;22易位的结果。大多数早期疾病患者在治疗后获得持久缓解使用伊马替尼（一种 BCR-ABL 小分子抑制剂）治疗。然而，在疾病晚期，耐药性和复发频繁发生。此外，如果治疗有效，活动性疾病的复发很常见。停了下来。因此，识别适合治疗干预的其他分子靶点可能会允许我们开发新的治疗策略，旨在克服疾病抵抗力并消除残留疾病。早期研究表明 BCR-ABL 促进不受调控的细胞周期进程和细胞通过损害 p27（一种肿瘤抑制因子和细胞周期蛋白依赖性激酶调节剂）的功能来促进增殖。然而，p27 解除管制的详细机制仍有待明确定义。 Agarwal 博士的初步数据表明，在原代 CML 细胞中，p27 失调涉及以下两方面：细胞核下调并增加细胞质错误定位。虽然核 p27 似乎是在 BCR-ABL 激酶活性的控制下，伊马替尼无法降低细胞质 p27 水平，这表明该过程以不依赖于激酶的方式进行调节。 CML 中核质 p27 比率较低祖细胞的比例让人想起几种实体癌的发现，其中这种比率与预后不良。 Agarwal 博士提出细胞质 p27 水平增加有助于 BCR-ABL 介导的 CML 中的白血病发生。为了支持这一点，Agarwal 博士表明，缺乏 p27 可缩短疾病潜伏期。小鼠 CML 模型，同时通过 p27 的强制核定位实验降低细胞质 p27 水平延长白血病小鼠的存活时间。这些发现与核的肿瘤抑制功能一致。 p27 和细胞质 p27 的伴随致癌功能。这些结果还表明，恢复核 p27 表达和减少细胞质表达可能会抵消 BCR-ABL 诱导的细胞转变。总的来说，Agarwal 博士的初步发现得出了一个假设，即 BCR-ABL 会破坏 p27 通过同时抑制其核肿瘤抑制功能并促进其细胞质肿瘤抑制功能发挥作用致癌功能。这一假设将通过三个精心设计的具体目标进行检验，这些目标同时利用了体外和体内方法：1) Agarwal 博士将应用分子和细胞生物学工具来确定 BCR-ABL 上调细胞质 p27 的机制。 2）她将剖析核能和核能的作用使用 p27 转基因小鼠白血病模型研究细胞质 p27 用于 BCR-ABL 驱动的白血病发生。 3）她将描述细胞质 p27 介导人类细胞转化的信号传导机制通过测试细胞质 p27 对 CML 细胞侵袭和生存途径的影响。阿加瓦尔博士的工作将提高对 p27 在 CML 发病机制中的作用的了解，并为开发治疗 CML 的新方法。由于 p27 生理功能的破坏是一个常见的主题人类癌症，这项研究的结果可能具有超越 CML 的影响。