Impact of aging on the outcomes of a mouse model of chronic myeloid leukemia

衰老对慢性粒细胞白血病小鼠模型结果的影响

基本信息

批准号：
9353341
负责人：
WENYONG CHEN
金额：
$ 9.86万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9353341
关键词：
Address Affect Age Aging BCR/ABL fusion gene Bone Marrow Cells Cell Compartmentation Cell Cycle Cells Chromosomal translocation Chromosomes, Human, Pair 22 Chromosomes, Human, Pair 9 Chronic Myeloid Leukemia Data Deacetylase Development Diagnosis Disease Disease Progression Drug resistance Elderly Feasibility Studies Foundations Frequencies Future Genes Goals HMGA2 gene Health Hematopoietic stem cells Human Imatinib Inbred BALB C Mice Knock-out Knockout Mice Light Longevity Lysine Maintenance Malignant - descriptor Malignant Neoplasms Metabolism Modeling Molecular Mus Oncogenic Outcome Pathogenesis Pathology Patients Pharmaceutical Preparations Pharmacotherapy Phase Play Population Process Protein Tyrosine Kinase Proteins Recurrent disease Research Risk Factors Role SIRT1 gene SLAM protein Severity of illness Side Source Testing Therapeutic Intervention Transplantation Tyrosine Kinase Inhibitor age effect aged anticancer research bcr-abl Fusion Proteins biological adaptation to stress dosage human disease improved improved outcome inhibitor/antagonist insight killings leukemia leukemia treatment leukemic stem cell leukemogenesis mouse model novel therapeutic intervention response retroviral transduction success targeted treatment treatment response

项目摘要

Chronic myelogenous leukemia (CML) occurs predominantly in the elderly with a medium age at diagnosis around 60 years. CML is caused by the oncogenic tyrosine kinase fusion gene BCR-ABL that transforms a normal hematopoietic stem cell (HSC) into a leukemic stem cell (LSC). Several decades of CML research has led to development of the tyrosine kinase inhibitor imatinib as the first successful targeted therapy of human cancer. Despite the great success of imatinib in CML treatment, the drug fails to eradicate LSCs and the disease relapses when the drug is ceased. However, the mechanisms of CML LSC drug resistance are not well understood, which would hamper our effort in finding a cure. Mouse models of CML played a pivotal role for illustrating roles of BCR-ABL in molecular pathogenesis of CML and for studying CML disease progression and therapeutic interventions. However, mouse models are generated in very young mice (2 to 3 months), and it is unknown how advanced age may influence CML in the mouse models and whether CML in older mice may provide an advantage for modeling the human disease in response to the treatment and LSC drug resistance. The goal of this application is to determine whether or not advanced age is an important influencing factor on leukemia progression and pathology, response to drug treatment, as well as LSC drug resistance. Our central hypothesis is that advanced age impacts the experimental outcomes of a mouse model of chronic myeloid leukemia that, in human, has aging as a major risk factor. We will test this hypothesis with a well characterized and widely used mouse model of CML by BCR-ABL transduction of BALB/c mouse bone marrow cells followed by transplantation to lethally irradiated BALB/c recipients. We have recently identified that CML LSCs in this mouse model reside exclusively in CD150- side population. We have discovered that protein lysine deacetylase SIRT1 is activated by BCR-ABL transformation in HSCs and SIRT1 knockout inhibits CML development and depletes CML LSCs in the BALB/c mouse CML model. We have shown that SIRT1 inhibition sensitizes CML cells, particularly LSCs, to imatinib and may help eradicate LSCs. In UH2 phase of this proposal, we will breed sufficient BALB/c mice and SIRT1 knockout mice for the feasibility and UH3 phase studies. In UH3 phase, we will continue the maintenance of aging mice and produce additional mice for aging and control. We will study three specific aims: 1) To determine the age impact on CML disease progression and LSCs. 2) To determine age impact on CML LSCs in response to tyrosine kinase inhibitor treatment. 3) To determine the impact of age on SIRT1 inhibition for eradicating CML LSCs. Successful completion of the proposed studies will shed new insight into the effect of age on CML LSC drug resistance and may lay a foundation for the use of aged mice for CML research for improved outcomes.

慢性粒细胞白血病（CML）主要发生于中老年人群。诊断年龄约60岁。 CML 是由致癌酪氨酸激酶融合基因 BCR-ABL 引起的，该基因将正常造血干细胞（HSC）转化为白血病干细胞（LSC）。 CML 数十年研究导致酪氨酸激酶抑制剂伊马替尼的开发，这是第一个成功的靶向药物人类癌症的治疗。尽管伊马替尼在 CML 治疗中取得了巨大成功，但该药物未能根除当停药时，LSC 和疾病会复发。然而，CML LSC 药物的机制耐药性尚未得到充分了解，这将阻碍我们寻找治疗方法的努力。 CML小鼠模型对于阐明 BCR-ABL 在 CML 分子发病机制中的作用以及研究 CML 发挥了关键作用疾病进展和治疗干预。然而，小鼠模型是在非常年幼的小鼠中生成的（2 至 3 个月），目前尚不清楚高龄如何影响小鼠模型中的 CML，以及是否老年小鼠的 CML 可能为模拟人类疾病对治疗的反应提供优势和LSC耐药性。此应用程序的目标是确定高龄是否是一个白血病进展和病理、药物治疗反应以及 LSC耐药性。我们的中心假设是，高龄会影响实验结果慢性粒细胞白血病的小鼠模型，在人类中，衰老是一个主要危险因素。我们将测试这个假设通过 BCR-ABL 转导建立了一个特征明确且广泛使用的 CML 小鼠模型 BALB/c 小鼠骨髓细胞，然后移植到接受致命辐射的 BALB/c 受体中。我们有最近发现，该小鼠模型中的 CML LSC 仅存在于 CD150 侧群体中。我们有发现蛋白质赖氨酸脱乙酰酶 SIRT1 通过 HSC 和 SIRT1 中的 BCR-ABL 转化而被激活敲除可抑制 BALB/c 小鼠 CML 模型中 CML 的发展并消除 CML LSC。我们有研究表明，SIRT1 抑制可使 CML 细胞（尤其是 LSC）对伊马替尼敏感，并可能有助于根除 LSC。在本提案的UH2阶段，我们将培育足够的BALB/c小鼠和SIRT1敲除小鼠以进行可行性研究和UH3阶段研究。在UH3阶段，我们将继续维持衰老小鼠并生产额外的小鼠衰老和控制。我们将研究三个具体目标：1) 确定年龄对 CML 疾病的影响进展和 LSC。 2) 确定年龄对酪氨酸激酶抑制剂反应对 CML LSC 的影响治疗。 3) 确定年龄对 SIRT1 抑制对根除 CML LSC 的影响。成功的拟议研究的完成将为年龄对 CML LSC 耐药性的影响提供新的见解并可能为使用老年小鼠进行 CML 研究以改善结果奠定基础。