1. Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition.
- Author
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Dzama MM, Steiner M, Rausch J, Sasca D, Schönfeld J, Kunz K, Taubert MC, McGeehan GM, Chen CW, Mupo A, Hähnel P, Theobald M, Kindler T, Koche RP, Vassiliou GS, Armstrong SA, and Kühn MWM
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Apoptosis drug effects, Cell Line, Tumor, Coculture Techniques, Drug Synergism, Humans, Leukemia, Myeloid, Acute genetics, Mice, Mice, Inbred NOD, Myeloid Ecotropic Viral Integration Site 1 Protein biosynthesis, Myeloid Ecotropic Viral Integration Site 1 Protein genetics, Neoplasm Proteins biosynthesis, Neoplasm Proteins genetics, Nuclear Proteins genetics, Nucleophosmin, Phosphorylation, Protein Kinase Inhibitors pharmacology, Protein Processing, Post-Translational, Random Allocation, Transcription, Genetic drug effects, fms-Like Tyrosine Kinase 3 biosynthesis, fms-Like Tyrosine Kinase 3 genetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Gene Expression Regulation, Leukemic drug effects, Histone-Lysine N-Methyltransferase antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Myeloid-Lymphoid Leukemia Protein antagonists & inhibitors, Neoplasm Proteins antagonists & inhibitors, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins antagonists & inhibitors, fms-Like Tyrosine Kinase 3 antagonists & inhibitors
- Abstract
The interaction of menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and provides a potential opportunity for treatment of NPM1-mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. In this study, transcriptional profiling after pharmacological inhibition of the menin-MLL complex revealed specific changes in gene expression, with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being the most pronounced. Combining menin-MLL inhibition with specific small-molecule kinase inhibitors of FLT3 phosphorylation resulted in a significantly superior reduction of phosphorylated FLT3 and transcriptional suppression of genes downstream of FLT3 signaling. The drug combination induced synergistic inhibition of proliferation, as well as enhanced apoptosis, compared with single-drug treatment in models of human and murine NPM1mut and MLL-r leukemias harboring an FLT3 mutation. Primary acute myeloid leukemia (AML) cells harvested from patients with NPM1mutFLT3mut AML showed significantly better responses to combined menin and FLT3 inhibition than to single-drug or vehicle control treatment, whereas AML cells with wild-type NPM1, MLL, and FLT3 were not affected by either of the 2 drugs. In vivo treatment of leukemic animals with MLL-r FLT3mut leukemia reduced leukemia burden significantly and prolonged survival compared with results in the single-drug and vehicle control groups. Our data suggest that combined menin-MLL and FLT3 inhibition represents a novel and promising therapeutic strategy for patients with NPM1mut or MLL-r leukemia and concurrent FLT3 mutation., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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