The histone demethylase JMJD1C in human Acute Myeloid Leukemia

PROJECT SUMMARY Current therapy for acute myeloid leukemia (AML) is inadequate. Despite newly available therapeutics agents, the overall survival rate for patients with the disease is still poor. It was previously shown that JMJD1C, a histone demethylase of KDM3 (lysine demethylase 3) family, is required for AML leukemogenesis but largely dispensable for steady state hematopoiesis and therefore, a potential therapeutic target in AML. In a recent study, loss of JMJD1C in leukemia cells was shown to lead to elevated RAS signaling pathway and increased sensitivity to inhibitors against the pathway. Furthermore, the presence of RAS activating mutations that are common in AML confer resistance to JMJD1C loss. These data led to the hypothesis that targeting RAS pathway in combination with JMJD1C would be more effective in eliminating leukemia cells harboring activating RAS mutations. This hypothesis will be tested by the following plan: i) efficacy of combining JMJD1C modulation with RAS pathway inhibitors in treating AML with RAS mutations will be tested in mouse as well as xenograft models of AML; ii) molecular mechanism of resistance to JMJD1C loss in AML with RAS mutations, as well as the role of biomolecule condensates, emerging key regulator of transcription and AML leukemogenesis, in mediating the molecular function of JMJD1C in AML will be studied. Overall, the proposed project, once accomplished, will provide rational for the design of novel combination therapy for AML with co-occurring activating RAS mutations.