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

慢性粒细胞白血病(CML)主要发生在中年以下的老年人 确诊时间约为60年。CML是由致癌的酪氨酸激酶融合基因bcr-abl引起的 将正常的造血干细胞(HSC)转化为白血病干细胞(LSC)。几十年的慢性粒细胞白血病 研究导致酪氨酸激酶抑制剂伊马替尼的开发成为首个成功的靶向药物 人类癌症的治疗。尽管伊马替尼在治疗慢性粒细胞白血病方面取得了巨大的成功，但该药物未能根除 当药物停用时，LSCs和疾病复发。然而，慢性粒细胞白血病LSC药物的作用机制 抗药性没有得到很好的理解，这将阻碍我们找到治愈方法的努力。慢性粒细胞白血病的小鼠模型 对于阐明bcr-abl在CML分子发病机制中的作用和研究CML具有举足轻重的作用。 疾病进展和治疗干预。然而，小鼠模型是在非常年轻的小鼠身上产生的 (2-3个月)，目前尚不清楚高龄对小鼠模型CML的影响，以及 老年小鼠的慢性粒细胞白血病可能为模拟人类疾病对治疗的反应提供了优势 以及对LSC的耐药性。此应用程序的目标是确定高龄是否为 白血病进展和病理、药物治疗反应的重要影响因素 LSC耐药。我们的中心假设是，高龄会影响 慢性髓系白血病的小鼠模型，在人类中，衰老是一个主要的危险因素。我们将对此进行测试 BCR-ABL转导CML小鼠模型的假说 将BALB/c小鼠骨髓细胞移植到致死剂量照射的BALB/c受体。我们有 最近发现，这种小鼠模型中的CML LSCs仅存在于CD150侧的群体中。我们有 在HSCs和SIRT1中发现蛋白赖氨酸脱乙酰基酶SIRT1被BCR-ABL转换激活 在BALB/c小鼠CML模型中，基因敲除可抑制CML的发展并耗尽CML LSCs。我们有 研究表明，抑制SIRT1使CML细胞，特别是LSCs对伊马替尼敏感，并可能有助于消除LSCs。 在该计划的UH2阶段，我们将培育足够的BALB/c小鼠和SIRT1基因敲除小鼠以进行可行性研究 和UH3相研究。在UH3阶段，我们将继续对老化小鼠进行维护，并生产额外的 小鼠用于衰老和对照。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)确定酪氨酸激酶抑制剂对慢性粒细胞白血病LSCs的年龄影响 治疗。3)研究AGE对SIRT1基因抑制CML LSCs的影响。成功 拟议研究的完成将为年龄对慢性粒细胞白血病耐药的影响提供新的见解 并可能为利用老龄小鼠进行CML研究以改善结果奠定基础。

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.