Mechanisms of action and therapeutic potential of AHR and DRD5 receptors in Acute Myeloid Leukemia with MLL-fusion gene

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Due to a still unfavorable prognosis, new, targeted therapies are urgently needed for Acute Myeloid Leukemia (AML). An MLL-fusion gene is present in the leukemic cells of a quarter of all children with AML. In preparatory studies, we could prioritize therapeutic targets downstream of the leukemogenic but hard-to-drug MLL-AF9 fusion gene. Two of these, the Aryl Hydrocarbon Receptor (AHR) and the Dopamine Receptor D5 (DRD5), have rarely been studied in the context of leukemia. Besides the recently described roles of AHR (pro-differentiational and anti-proliferative) and DRD5 (pro-proliferative and prognostic relevance in AML), we could provide evidence of pro-apoptotic and anti-proliferative effects of an AHR agonist and a DRD5 antagonist on leukemic cells with MLL-fusion. This project aims to elucidate the mode of action (signal transduction pathways) as well as the therapeutic efficacy and applicability of the two potential drug targets AHR and DRD5 in the context of AML. Due to the presence of well characterized receptor modulators, a fast transition into the clinic seems within reach.