Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia Journal Article
| Authors: | Uckelmann, H. J.; Kim, S. M.; Wong, E. M.; Hatton, C.; Giovinazzo, H.; Gadrey, J. Y.; Krivtsov, A. V.; Rücker, F. G.; Döhner, K.; McGeehan, G. M.; Levine, R. L.; Bullinger, L.; Vassiliou, G. S.; Armstrong, S. A. |
| Article Title: | Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia |
| 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 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. © 2020 American Association for the Advancement of Science. All rights reserved. |
| Keywords: | controlled study; unclassified drug; gene mutation; mutation; nonhuman; drug targeting; cell proliferation; animal cell; mouse; gene; mus; animal experiment; animal model; antineoplastic activity; chromatin; leukemia cell; methionine; disease treatment; biological development; mouse model; cell; molecularly targeted therapy; numerical model; acute myeloid leukemia; cell self-renewal; preleukemia; antileukemic agent; npm1 gene; oral health; cancer; priority journal; article; vtp 50469 |
| Journal Title: | Science |
| Volume: | 367 |
| Issue: | 6477 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2020-01-31 |
| Start Page: | 586 |
| End Page: | 590 |
| Language: | English |
| DOI: | 10.1126/science.aax5863 |
| PUBMED: | 32001657 |
| PROVIDER: | scopus |
| PMCID: | PMC7754791 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
