SIRT5 as a Therapeutic Target in Acute Myeloid Leukemia

 描述（由申请人提供）：急性髓性白血病（AML）是一种预后不良的侵袭性血癌，年轻患者的存活率约为50%，但60岁以上患者的存活率低于20%。此外，AML干细胞通常在骨髓的保护环境中存活化疗，即使在对治疗有良好初始反应的患者中也会导致复发。目前的治疗标准，化疗或干细胞移植，三十多年来基本保持不变。不幸的是，每年估计有18，000名美国人被诊断患有AML，其中超过10，000人将死于他们的疾病，这迫切需要更好，更有针对性的治疗。DNA测序已经在AML患者中发现了许多突变，但到目前为止，这些知识还没有转化为重大的治疗进展。这可能反映了疾病的复杂性，以及许多突变基因已被证明难以治疗的事实。为了克服过去努力的一些局限性，我们采取了一种功能优先的方法，对患者的AML细胞进行筛选，并逐一灭活数千个基因，以便我们能够识别那些对AML细胞存活至关重要的基因。重要的是，我们的试验是在骨髓基质细胞存在下进行的，以模拟骨髓的保护环境。该筛选揭示了AML样品的一个子集依赖于SIRT5的活性，SIRT5是一种多功能酶，调节线粒体和胞质溶胶中的重要代谢途径。在这些细胞中，SIRT5敲低导致生长抑制和细胞死亡，而正常健康的骨髓细胞不受影响。我们建议使用SIRT5敲低和代谢谱来确定AML干细胞中的其他关键存活途径，目的是利用这些途径与小分子。这些数据将与体细胞突变筛选，基因表达分析和代谢组学分析相关，以了解SIRT5依赖性的机制基础。我们的研究有可能建立SIRT5是AML治疗靶点的原则证据，为开发临床可行的SIRT5抑制剂治疗AML和可能的其他类型的癌症提供科学依据。重要的是，SIRT5缺失的小鼠是可行的，没有重大缺陷，这表明SIRT5抑制剂具有良好的耐受性。

 DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis, with survival rates in younger patients at approximately 50%, but less than 20% in patients over 60 years old. Additionally, AML stem cells often survive chemotherapy in the protective environment of the bone marrow, causing relapse even in patients with a good initial response to therapy. The current standard of care, chemotherapy or stem cell transplant, has remained largely unchanged for more than three decades. Unfortunately, of the estimated 18,000 Americans diagnosed with AML every year, more than 10,000 will die of their disease, defining an urgent need for better and more targeted therapies. DNA sequencing has identified numerous mutations in AML patients, but as yet this knowledge has not translated into major therapeutic advances. This probably reflects the complexity of the disease and the fact that many of the mutated genes have proven difficult to target therapeutically. To overcome some of the limitations of past efforts, we have taken a function-first approach, where AML cells from patients are screened and thousands of genes are inactivated, one-by-one, so that we can identify those that are critical for AML cell survival. Importantly, our assays are done in the presence of bone marrow stromal cells to mimic the protective environment of the bone marrow. This screen has revealed that a subset of AML samples are dependent on the activity of SIRT5, a multifunctional enzyme that regulates vital metabolic pathways in the mitochondria and cytosol. In these cells, SIRT5 knockdown caused growth inhibition and cell death, while normal, healthy bone marrow cells were unaffected. We propose to use SIRT5 knockdown and metabolic profiling to determine other key survival pathways in AML stem cells with the intention of exploiting these pathways with small molecules. These data will be correlated with somatic mutation screening, gene expression analysis and metabolomics profiling to understand the mechanistic underpinnings of SIRT5 dependence. Our studies have the potential to establish proof of principle that SIRT5 is a therapeutic target in AML, providing a scientific rationale for the development of clinically-viabl SIRT5 inhibitors to treat AML and possibly other types of cancer. Importantly, mice with deletion of SIRT5 are viable and have no major defects, suggesting that SIRT5 inhibitors would be well tolerated.