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

• 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
• 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

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.

项目摘要/摘要 职业目标：Agarwal博士的长期目标是阐明白血病的新颖分子机制 发病机理，以便将这些知识应用于发现新疗法，从而改善 临床结果。阿加瓦尔博士的职业目标是建立一个专注于 了解癌症发病机理。对于K99独立奖，Agarwal博士已经描述了 一项为期五年的培训计划，使她能够获得成功所需的专业知识 独立癌症研究员。在此奖项期间，她将能够扩大自己在癌症生物学方面的知识， 获得各种新型技术的专业知识，可用于她的未来研究，并产生一群 数据作为未来研究的基础和校外资金的应用。获取的知识和数据 在K99/R00奖中生产的将有助于实现她的长期目标。 环境：俄勒冈州健康与科学大学骑士癌症研究所有165个小学教师 研究人员在各种领域具有专业知识。 Agarwal博士的导师Brain Druker博士是 骑士癌症研究所主任。 Druker博士在癌症领域拥有20多年的经验 研究并指导了许多学生和研究员，以达到独立研究者的身份。他将继续 为Agarwal博士提供智力和领导力培训，以过渡到独立的职业 研究员。 Agarwal博士与合并的合作者和顾问聚集了一支优秀的团队 专业知识可以就拟议的研究以及她的职业生涯的各个方面提供建议。另外，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 为成功的教师职业做准备的人。 Agarwal博士认为，拟议的项目是 非常适合在白血病发病机理领域启动她独立的研究生涯。 研究：拟议的研究的目的是确定慢性p27放松管制的机理 髓样白血病（CML），并确定p27在CML发病机理中的作用。 CML是由BCR-ABL引起的造血干细胞的疾病，BCR-ABL是一种组成型活性酪氨酸激酶，它是一种疾病 是9; 22易位的结果。大多数早期疾病的患者在 用伊马替尼（BCR-ABL的小分子抑制剂）治疗。但是，在疾病的晚期阶段， 耐药性和复发频繁。此外，如果治疗为 停了下来。因此，鉴定适合治疗干预的其他分子靶标可以允许 我们制定旨在克服抗病性并消除残留的新型治疗策略 疾病。较早的研究表明，BCR-ABL促进了不受管制的细胞周期进程和细胞 通过损害P27的功能，肿瘤抑制剂和细胞周期蛋白依赖激酶的调节剂的增殖。 但是，p27放松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放松管制既涉及 细胞核中的下调并增加了细胞质错误定位。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，表明 此过程以与激酶无关的方式进行调节。 CML的低核与周期p27比率 祖细胞让人联想到几种类型的固体癌症中的发现，其中这种比率与A相关 预后不良。 Agarwal博士提出，增加的细胞质P27水平有助于BCR-ABL-介导 CML中的白血病发生。为此，Agarwal博士表明，缺乏p27会降低疾病潜伏期 鼠CML模型，同时通过强迫核定位置p27降低细胞质p27水平 延长白血病小鼠的生存。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。这些结果还表明还原 核p27表达和降低细胞质表达可能抵消BCR-ABL诱导的细胞 转型。总的来说，Agarwal博士的初步发现导致了一个假设，其中BCR-ABL破坏了 p27通过同时抑制其核肿瘤抑制器功能并促进其细胞质的功能 致癌功能。该假设将通过三个精心设计的特定目标来检验 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）她将剖析核和 使用p27转基因鼠白血病模型用于BCR驱动的白血病的细胞质p27。 3）她 将描述细胞质p27介导人细胞转化的信号传导机制 CML细胞通过测试细胞质p27对侵袭和存活途径的影响。 Agarwal博士的工作将 提高人们对P27在CML发病机理中的作用的了解，并为 开发治疗CML的新方法。由于生理p27功能的破坏是一个常见的主题 人类癌症，这项研究的发现可能具有CML以外的含义。