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

项目摘要 慢性粒细胞白血病（CML）主要发生在诊断时年龄中等的老年人中 大约60年。CML是由致癌酪氨酸激酶融合基因BCR-ABL引起的，BCR-ABL将一种 正常造血干细胞（HSC）转化为白血病干细胞（LSC）。几十年的CML研究 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治疗人类 癌尽管伊马替尼在CML治疗中取得了巨大成功，但该药物未能根除LSC， 停药后疾病复发。然而，CML LSC耐药的机制并不 这会妨碍我们找到治愈方法慢性粒细胞白血病的小鼠模型发挥了关键作用 阐明BCR-ABL在CML分子发病机制中的作用和研究CML疾病进展 和治疗干预。然而，小鼠模型是在非常年幼的小鼠（2至3个月）中产生的，并且 尚不清楚高龄如何影响小鼠模型中的CML，以及老年小鼠中的CML是否可能 为响应治疗和LSC耐药性的人类疾病建模提供了优势。 本申请的目的是确定高龄是否是一个重要的影响因素， 白血病进展和病理学、对药物治疗的反应以及LSC耐药性。我们的中央 一种假设是，高龄影响慢性髓系白血病小鼠模型的实验结果， 在人类中，衰老是主要的危险因素。我们将用一个特征良好的 和广泛使用的CML小鼠模型，通过BCR-ABL转导BALB/c小鼠骨髓细胞， 通过移植到致死性照射的BALB/c受体。我们最近发现，CML LSC在这种情况下， 小鼠模型仅存在于CD 150侧群体中。我们发现蛋白质赖氨酸 HSC中BCR-ABL转化激活脱乙酰酶SIRT 1，SIRT 1敲除抑制CML 在BALB/c小鼠CML模型中的CML LSC的发育和耗竭。我们已经证明SIRT 1抑制 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UH 2阶段， 我们将为可行性研究和UH 3期研究培育足够数量的BALB/c小鼠和SIRT 1基因敲除小鼠 问题研究在UH 3阶段，我们将继续维持老化小鼠，并生产额外的老化小鼠 防治的攻坚我们将研究三个具体目标：1）确定年龄对CML疾病进展的影响 和LSC。2)确定年龄对CML LSC对酪氨酸激酶抑制剂治疗的反应的影响。3)到 确定年龄对SIRT 1抑制根除CML LSC的影响。成功完成 拟议中的研究将揭示年龄对CML LSC耐药性的影响，并可能奠定一个新的认识。 基金会使用老年小鼠进行CML研究，以改善结果。

Project Summary 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.