Subject(s)
Benzimidazoles/therapeutic use , Enzyme Inhibitors/therapeutic use , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Leukemia/drug therapy , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Benzimidazoles/pharmacokinetics , Drugs, Investigational/pharmacokinetics , Drugs, Investigational/therapeutic use , Enzyme Inhibitors/pharmacokinetics , Humans , Jurkat Cells , K562 Cells , Leukemia/pathology , Mice , Treatment Outcome , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
The initiating mutations that contribute to cancer development are sometimes present in premalignant cells. Whether therapies targeting these mutations can eradicate premalignant cells is unclear. Acute myeloid leukemia (AML) is an attractive system for investigating the effect of preventative treatment because this disease is often preceded by a premalignant state (clonal hematopoiesis or myelodysplastic syndrome). In Npm1c/Dnmt3a mutant knock-in mice, a model of AML development, leukemia is preceded by a period of extended myeloid progenitor cell proliferation and self-renewal. We found that this self-renewal can be reversed by oral administration of a small molecule (VTP-50469) that targets the MLL1-Menin chromatin complex. These preclinical results support the hypothesis that individuals at high risk of developing AML might benefit from targeted epigenetic therapy in a preventative setting.
Subject(s)
Genetic Therapy/methods , Leukemia, Experimental/prevention & control , Leukemia, Myeloid, Acute/prevention & control , Nuclear Proteins/genetics , Preleukemia/therapy , Animals , Chromatin/metabolism , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methyltransferase 3A , Gene Knock-In Techniques , Histone-Lysine N-Methyltransferase/metabolism , Leukemia, Experimental/genetics , Leukemia, Myeloid, Acute/genetics , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Mutation , Myeloid Progenitor Cells/pathology , Myeloid-Lymphoid Leukemia Protein/metabolism , Nucleophosmin , Preleukemia/genetics , Preleukemia/pathology , Proto-Oncogene Proteins/metabolismABSTRACT
Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.
