Combination of SD70 and MI-503 exerts a synergistic effect against MLL:: AF9-driven AML
Acute myeloid leukemia (AML), a heterogeneous hematologic malignancy, is the most common form of acute leukemia in adults. MLL rearrangements (MLL-r) are observed in approximately 10% of AML and are associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusions recruit KDM4C to mediate epigenetic reprogramming, which is required for maintenance of MLL-r leukemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI-503, a potent Menin-MLL inhibitor, induced synergistically enhanced apoptosis in MLL-r leukemia cells without affecting normal CD34+ cells. In vivo treatment with SD70 and MI-503 significantly prolongs survival in AML xenograft models. Differential Gene expression analysis by RNA-seq following combined pharmacological inhibition of SD70 and MI-503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI-503 is a potential dual-target therapy for MLL-r AML. Overall design: To investigate the molecular mechanism underlying the synergistic effect of SD70 and MI-503, we performed RNA-seq analysis on MOLM13 cells treated with DMSO, single agent alone, or the combination.