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Therapeutic targeting of preleukemia cells in a mouse model of mutant acute myeloid leukemia

Item Type:Article
Title:Therapeutic targeting of preleukemia cells in a mouse model of mutant acute myeloid leukemia
Creators Name:Uckelmann, H.J. and Kim, S.M. and Wong, E.M. and Hatton, C. and Giovinazzo, H. and Gadrey, J.Y. and Krivtsov, A.V. and Rücker, F.G. and Döhner, K. and McGeehan, G.M. and Levine, R.L. and Bullinger, L. and Vassiliou, G.S. and Armstrong, S.A.
Abstract: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 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.
Keywords:Acute Myeloid Leukemia, Chromatin, DNA (Cytosine-5-)-Methyltransferases, DNA Methyltransferase 3A, Experimental Leukemia, Gene Knock-In Techniques, Genetic Therapy, Histone-Lysine N-Methyltransferase, Inbred C57BL Mice, Mutant Strains Mice, Mutation, Myeloid Progenitor Cells, Myeloid-Lymphoid Leukemia Protein, Nuclear Proteins, Nucleophosmin, Preleukemia, Proto-Oncogene Proteins, Animals, Mice
Publisher:American Association for the Advancement of Science
Page Range:586-590
Date:31 January 2020
Official Publication:https://doi.org/10.1126/science.aax5863
PubMed:View item in PubMed

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