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

• 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
• 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

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）主要发生在中年的老年人中， 60岁左右的诊断。CML由致癌酪氨酸激酶融合基因BCR-ABL引起， 将正常造血干细胞（HSC）转化为白血病干细胞（LSC）。几十年的慢性粒细胞白血病 研究已经导致酪氨酸激酶抑制剂伊马替尼的发展，作为第一个成功的靶向 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 LSC和疾病复发时，药物停止。然而，CML LSC药物的机制 人们对耐药性的了解还不够，这将妨碍我们寻找治疗方法的努力。CML小鼠模型 为阐明BCR-ABL在CML分子发病机制中的作用及研究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轻的小鼠中产生的， （2至3个月），并且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了优势 和LSC耐药性。此应用程序的目标是确定高龄是否是一个 白血病进展和病理学重要影响因素，对药物治疗的反应，以及 LSC耐药性。我们的中心假设是，高龄会影响实验结果， 慢性髓细胞白血病的小鼠模型，在人类中，衰老是一个主要的风险因素。我们将测试这个 通过BCR-ABL转导的CML小鼠模型的充分表征和广泛使用的假设， BALB/c小鼠骨髓细胞，然后移植到致死照射的BALB/c受体。我们有 最近发现，该小鼠模型中的CML LSC仅存在于CD 150侧群体中。我们有 发现蛋白质赖氨酸脱乙酰基酶SIRT 1在HSC中被BCR-ABL转化激活，SIRT 1 在BALB/c小鼠CML模型中，敲除抑制CML发展并耗尽CML LSC。我们有 SIRT 1抑制可使CML细胞，特别是LSC对伊马替尼敏感，并可能有助于根除LSC。 在本方案的UH 2阶段，我们将繁殖足够的BALB/c小鼠和SIRT 1基因敲除小鼠，以确保可行性 UH 3阶段研究。在UH 3阶段，我们将继续维持老龄小鼠，并产生额外的 衰老和对照小鼠。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CML LSC对酪氨酸激酶抑制剂应答的影响 治疗3)确定年龄对SIRT 1抑制根除CML LSC的影响。成功 这些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。