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

点击翻译按钮获取中文摘要

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.