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: 9203366
• 负责人: WENYONG CHEN
• 金额: $ 5.14万
• 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/9203366
• 关键词: 5 year old; Address; Affect; Age; Aging; Bone Marrow Cells; Breeding; Cell Cycle; Cells; 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; 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; SLAM protein; Severity of illness; Side; Source; Stem cells; Testing; Therapeutic Intervention; Transplantation; Tyrosine Kinase Inhibitor; Work; age effect; aged; anticancer research; bcr-abl Fusion Proteins; biological adaptation to stress; dosage; fusion gene; human disease; improved; improved outcome; inhibitor/antagonist; insight; killings; leukemia; leukemia treatment; leukemic stem cell; leukemogenesis; mouse model; novel therapeutic intervention; response; retroviral transduction; stem; 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.

慢性骨髓性白血病（CML）主要发生在中年的老年人 诊断约60年。 CML是由致癌酪氨酸激酶融合基因BCR-ABL引起的 将正常的造血干细胞（HSC）转化为白细胞干细胞（LSC）。几十年的CML 研究导致了酪氨酸激酶抑制剂伊马替尼的发展，这是第一个成功的目标 人类癌症的治疗。尽管伊马替尼在CML治疗中取得了巨大的成功，但该药物仍未消除 当药物停止时，LSC和疾病复发。但是，CML LSC药物的机制 阻力不太了解，这会阻碍我们在找到治愈方法方面的努力。 CML的鼠标模型 在说明BCR-ABL在CML分子发病机理和研究CML中的作用中起着关键作用 疾病进展和治疗干预措施。但是，鼠标是在非常年轻的小鼠中产生的 （2到3个月），尚不清楚高龄如何影响鼠标模型中的CML 老鼠中的CML可能会为对治疗的响应进行建模人类疾病提供优势 和LSC耐药性。该应用的目的是确定高龄是否是 对白血病进展和病理学的重要影响因素，对药物治疗的反应以及 LSC耐药性。我们的中心假设是，高级年龄会影响 慢性髓样白血病的小鼠模型，在人类中，衰老是主要危险因素。我们将测试这个 通过BCR-ABL转导的CML的特征且广泛使用的小鼠模型的假设 BALB/C小鼠骨髓细胞，然后移植到致命的辐照BALB/C受体中。我们有 最近确定，该小鼠模型中的CML LSC仅存在CD150-侧种群中。我们有 发现蛋白质赖氨酸脱乙酰基酶SIRT1通过HSC和SIRT1中的BCR-ABL转化激活 敲除抑制CML的发育，并在BALB/C小鼠CML模型中耗尽CML LSC。我们有 表明SIRT1抑制使CML细胞（特别是LSC）敏感到伊马替尼，并可能有助于消除LSC。 在该提案的UH2阶段，我们将繁殖足够 和UH3相研究。在UH3阶段，我们将继续维持老化小鼠并产生更多 老化和控制的小鼠。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）确定响应酪氨酸激酶抑制剂对CML LSC的年龄影响 治疗。 3）确定年龄对消除CML LSC的抑制作用的影响。成功的 拟议的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研究奠定基础，以改善结果。