Characterizing vitamin B6 pathway dependency in acute myeloid leukemia

项目摘要/摘要 急性髓系白血病(AML)是最具破坏性的血癌之一，它影响着大约100万人和 导致全世界每年有147,000人死亡。急性髓系白血病的特征是血液中髓系细胞的异常产生。 白血病细胞和白血病细胞在骨髓和外周血中的快速生长。AML是一种侵袭性很强的癌症， 它进展迅速，AML患者在几周到几个月内就会死亡。目前，急性髓细胞白血病的治疗选择是 非常有限。只有大约35%的60岁以下的AML患者和10%的60岁以上的AML患者从标准 化疗。因此，迫切而又未得到满足的医学需要是开发新的治疗方法，尤其是 对急性髓细胞白血病患者进行疗效高、毒性低的联合治疗。我们提出的长期目标是 研究是研究异常维生素途径作为AML的代谢依赖，调查关键的调节因素 支持急性髓系白血病细胞异常增殖的维生素途径，并确定急性髓细胞白血病的药物治疗靶点。我们 最近发现维生素B6途径是急性髓系白血病的一种新的依赖性。基于这一发现，我们假设 维生素B6途径是一种特异的抗白血病靶点，在治疗急性髓系白血病方面具有广阔的应用前景。要评估 假设，我们已经确定了对AML细胞至关重要的维生素B6依赖代谢途径中的多种关键酶， 但不适用于正常骨髓的造血干、祖细胞和免疫细胞的增殖。耗尽这些资源 关键酶对急性髓系白血病的增殖有很强的抑制作用。我们还验证了维生素B6途径是一种 药理上可行的途径，并表明维生素B6途径抑制剂显示出良好的治疗前景 体内多种基因工程急性髓细胞白血病模型的疗效。这些强劲的初步数据鼓励我们追求三个 特异性目的是进一步表征维生素B6途径：1)表征维生素B6的上游和下游调控因子 2)评价维生素B6途径与bcl2在AML治疗中的协同作用。 进一步提高其疗效；3)进行功能基因组学筛选，以确定维生素B6途径的协同作用 AML中的效应器。我们建议从维生素B6途径和代谢编程这一过程的角度来研究AML 这对AML细胞的增殖是新的和必不可少的。拟议的研究将集中在机械和机械两个方面 了解维生素B6途径与急性髓系白血病不同协同效应相关的治疗靶点。 这项提案的主要目标是确定独特的维生素B6上游调节因子和下游效应因子为 以及其治疗AML的协同效应。这项提议意义重大，因为它不仅揭示了 该药物不仅具有抗白血病的作用机制，而且还能精确定位治疗靶点，以协同增强AML的抗白血病作用。

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is one of the most devastating blood cancers, and it affects around one million people and results in 147,000 deaths per year worldwide. AML is characterized by the abnormal production of myeloid lineage of blood cells and the rapid growth of leukemia blasts in bone marrow and peripheral blood. AML is a very aggressive cancer, and it progresses rapidly and AML patients become fatal within weeks to months. Currently, therapeutic options for AML are very limited. Only about 35% of AML patients under 60 years-old and 10% over 60 years-old benefit from standard chemotherapy. Thus, there is an urgent and unmet medical need to develop new therapeutic approaches particularly combination therapies with advanced efficacy and reduced toxicity for AML patients. Our long-term goals of the proposed research are to study abnormal vitamin pathways as metabolic dependencies in AML, to investigate critical regulators of vitamin pathways in supporting AML cell aberrant proliferation, and to identify druggable therapeutic targets in AML. We have recently uncovered vitamin B6 pathway as a novel dependency in AML. Based on this finding, we hypothesize that vitamin B6 pathway is a specific anti-leukemia target and has promising therapeutic potential to treat AML. To assess the hypothesis, we have identified multiple key enzymes in vitamin B6 dependent metabolic pathways essential for AML cell, but not for normal bone marrow hematopoietic stem and progenitor cell and immune cell, proliferation. Depletion of these key enzymes exhibited robust inhibition on AML proliferation. We have also validated vitamin B6 pathway as a pharmacologically actionable pathway and showed that vitamin B6 pathway inhibitors exhibit promising therapeutic efficacy in multiple genetically engineered AML models in vivo. These robust preliminary data encourage us to pursue three Specific Aims to further characterize vitamin B6 pathway: 1) to characterize both upstream and downstream regulators of vitamin B6 pathway in AML; 2) to evaluate the synergy between vitamin B6 pathway and BCL-2 in AML therapeutics to further enhance its efficacy; and 3) to perform functional genomics screens to identify vitamin B6 pathway synergistic effectors in AML. We propose to study AML from the aspect of vitamin B6 pathway and metabolic programming, a process which is novel and essential for AML cell proliferation. The proposed research will be focusing on both mechanistic understanding and therapeutic targeting of vitamin B6 pathway in association with different synergistic effectors in AML. The major goals of this proposal are to identify the unique vitamin B6 upstream regulators and downstream effectors as well as its synergistic effectors to treat AML. The proposal is significant because it will not only uncover the underlying mechanism but also pinpoint therapeutic targets to synergistically enhance the anti-leukemia effects in AML.