Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia

• Published in: Science (American Association for the Advancement of Science) Vol. 367; no. 6477; pp. 586 - 590
• Main Authors: Uckelmann, Hannah J., Kim, Stephanie M., Wong, Eric M., Hatton, Charles, Giovinazzo, Hugh, Gadrey, Jayant Y., Krivtsov, Andrei V., Rücker, Frank G., Döhner, Konstanze, McGeehan, Gerard M., Levine, Ross L., Bullinger, Lars, Vassiliou, George S., Armstrong, Scott A.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 31.01.2020
• Subjects: Acute myeloid leukemia; Animal models; Animals; Anticancer properties; Antitumor activity; Blood cancer; Blood cells; Cancer; Cell proliferation; Chromatin; Chromatin - metabolism; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA Methyltransferase 3A; Drug development; Epigenetics; Gene Knock-In Techniques; Genetic Therapy - methods; Hematopoiesis; Hemopoiesis; Histone-Lysine N-Methyltransferase - metabolism; Interception; Leukemia; Leukemia, Experimental - genetics; Leukemia, Experimental - prevention & control; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - prevention & control; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Myelodysplastic syndrome; Myeloid Progenitor Cells - pathology; Myeloid-Lymphoid Leukemia Protein - metabolism; Nuclear Proteins - genetics; Nucleophosmin; Oral administration; Preleukemia - genetics; Preleukemia - pathology; Preleukemia - therapy; Progenitor cells; Proto-Oncogene Proteins - metabolism; Therapeutic targets; Therapy
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aax5863

Recent technological advances have made it possible to detect, in healthy individuals, premalignant blood cells that are likely to progress to hematologic cancer. These advances in early detection have fueled interest in “cancer interception,” the idea that drugs designed to treat advanced cancer might also be useful for cancer prevention. Uckelmann et al. now provide support for this concept in a study of mice genetically predisposed to develop acute myeloid leukemia. Early administration of an epigenetic therapy that had previously been shown to have anticancer activity in advanced leukemia models was able to eliminate preleukemia cells and extend survival of the mice. Science , this issue p. 586 An epigenetic therapy can eliminate preleukemia cells and delay leukemia development in a mouse model. 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.