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Therapeutic Targeting of Acute Leukemia with Upregulated HOX Genes
The protein-protein interaction between menin and Mixed Lineage Leukemia 1 (MLL1) plays a critical role in acute leukemias with upregulated HOX genes, including the MLL1-rearranged, NPM1-mutated and NUP98-rearranged leukemias. Indeed, very effective menin inhibitors have been developed, including our own efforts, and translated to the clinic, demonstrating promising efficacy in AML patients with NPM1-mutations and MLL1 translocations. However, recent clinical studies revealed resistance that develops to the treatment with the menin inhibitor in a sub-set of AML patients resulting from the point mutations in the inhibitor binding site on menin. Thus, combinations with other agents or new generations of menin inhibitors might be needed to overcome the resistance in AML patients. Here, combinatorial studies of the menin inhibitor with targeted agents and other approaches to overcome the resistance will be discussed. These data provide a strong foundation for clinical translation of the menin inhibitor-based combinations for patients with upregulated HOX genes.