Identification and activation of “good oncogenic” microRNAs as improved therapy for acute myeloidleukemia

鉴定和激活“良好致癌”microRNA 作为急性髓系白血病的改进疗法

• 批准号: 407318689
• 负责人: Professor Dr. Gerhard Behre
• 金额: --
• 依托单位: Klinik für Innere Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/407318689?language=en
• 关键词: Identification; activation; good; oncogenic; microRNAs

Acute myeloid leukemia (AML) is a malignant disease of thehematopoietic system resulting in the accumulation of leukemic blastsin the bone marrow and the peripheral blood. The outcome of patientssuffering from AML is still very poor and therapy needs to beimproved. AML can be divided into different subgroups depending onthe molecular background and its prognostic impact. While severalcausative oncogenic mutations are connected to a poor prognosis,others lead to a promising response to current chemotherapeutictherapies. It is commonly unknown why different oncogenictransformations result in these big differences in treatment response.MicroRNAs, a class of small non-coding RNAs, were identified asimportant regulators of normal hematopoiesis and leukemiadevelopment. We and others have already shown that microRNAscan act as oncogenes or tumor suppressors in AML. In the presentproposal, we aim to develop a revolutionary new concept of cancertreatment: Based on the knowledge that several oncogenictransformation associated gene modifications are connected to a wellpromising treatment response, we aim to activate specific goodoncogenic microRNAs instead of blocking them and to combine thiswith specific anti cancer drugs. In our preliminary work, we identifiedexemplarily a good oncogenic microRNA, miR-182, that inducesproliferation but enhances the response to anti-tumor agents. Thus,miR-182 seems to reveal a Janus-faced nature of being oncogenicbut still therapeutic at the same time. Because microRNAs have theability to target multiple genes, we raise the hypothesis that anoncogenic microRNA has the potential to induce hyperproliferation oftarget cells and to increase the susceptibility to chemotherapeuticagents by blocking drug resistance associated genes like ABCtransporters or DNA-repair proteins (BRCA1, RAD51). Theconsequence would be a more effective treatment response of allcancer cells including dormant cancer stem cells. Taken together, wetry to establish the base of a new therapeutic strategy to enhance theAML treatment success.

急性髓系白血病（acute myeloid leukemia，AML）是一种造血系统的恶性疾病，主要表现为白血病细胞在骨髓和外周血中的聚集。AML患者的预后仍然很差，治疗需要改进。AML可根据分子背景及其预后影响分为不同的亚组。虽然一些致癌基因突变与不良预后有关，但其他突变导致对当前化疗的有希望的反应。目前还不清楚为什么不同的致癌转化会导致治疗反应的巨大差异。microRNA是一类小的非编码RNA，被鉴定为正常造血和白血病发展的重要调节因子。我们和其他人已经证明microRNA在AML中可以作为癌基因或肿瘤抑制因子。在本提案中，我们的目标是开发一种革命性的癌症治疗新概念：基于几种致癌转化相关基因修饰与良好的治疗反应有关的知识，我们的目标是激活特定的良性致癌microRNA而不是阻断它们，并将其与特定的抗癌药物联合收割机结合起来。在我们的前期工作中，我们成功地鉴定了一种良好的致癌microRNA，miR-182，它可以诱导增殖，但可以增强对抗肿瘤药物的反应。因此，miR-182似乎揭示了一个两面性的致癌性，但同时仍然具有治疗性。由于microRNA具有靶向多个基因的能力，我们提出一个假设，即致癌microRNA具有诱导靶细胞过度增殖的潜力，并通过阻断ABC转运蛋白或DNA修复蛋白（BRCA 1，RAD 51）等耐药相关基因而增加对化疗药物的敏感性。结果将是对所有癌细胞包括休眠癌干细胞的更有效的治疗反应。综上所述，我们试图建立一个新的治疗策略的基础，以提高AML治疗的成功率。