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

急性髓系白血病(AML)是一种血液系统的恶性疾病，导致白血病母细胞在骨髓和外周血中聚集。急性髓系白血病患者的预后仍然很差，治疗需要改进。根据AML的分子背景及其对预后的影响，AML可分为不同的亚型。虽然有几个致癌基因突变与不良预后有关，但其他致癌基因突变会导致对当前化疗的有希望的反应。人们通常不知道为什么不同的致癌转化会导致治疗反应的如此大的差异。MicroRNAs是一类小的非编码RNA，被发现是正常造血和白血病发生的重要调节因子。我们和其他人已经证明，microRNAs可以在AML中扮演癌基因或肿瘤抑制因子的角色。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：基于几个致癌转化相关基因修饰与良好的治疗反应相关的知识，我们的目标是激活特定的致癌microRNAs，而不是阻断它们，并将其与特定的抗癌药物结合。在我们的初步工作中，我们鉴定了一种良好的致癌microRNA miR-182，它可以诱导增殖，但增强了对抗肿瘤药物的反应。因此，miR-182似乎揭示了一种Janus脸的性质，即既是致癌的，又是治疗的。由于microRNA具有靶向多个基因的能力，我们提出假设，即非癌基因microRNA具有诱导靶细胞过度增殖的潜力，并通过阻断与耐药相关的基因如ABC转运蛋白或DNA修复蛋白(BRCA1，RAD51)而增加对化疗药物的敏感性。该序列将是包括处于休眠状态的癌症干细胞在内的所有癌细胞的更有效的治疗反应。综上所述，我们试图为新的治疗策略奠定基础，以提高AML的治疗成功率。

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.