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

Science. 2020 Jan 31;367(6477):586-590. doi: 10.1126/science.aax5863.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatin / metabolism
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • Gene Knock-In Techniques
  • Genetic Therapy / methods*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Leukemia, Experimental / genetics
  • Leukemia, Experimental / prevention & control*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutation
  • Myeloid Progenitor Cells / pathology
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Nuclear Proteins / genetics*
  • Preleukemia / genetics
  • Preleukemia / pathology
  • Preleukemia / therapy*
  • Proto-Oncogene Proteins / metabolism


  • Chromatin
  • Men1 protein, mouse
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • nucleophosmin
  • Myeloid-Lymphoid Leukemia Protein
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse