A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia

Cancer Cell. 2019 Dec 9;36(6):660-673.e11. doi: 10.1016/j.ccell.2019.11.001.


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.

Keywords: DOT1L; MLL fusion; Menin inhibitor; acute myeloid leukemia (AML); chromatin remodeling; infant B cell acute lymphoblastic leukemia (B-ALL); leukemia.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Chromatin / drug effects*
  • Chromatin / genetics
  • Gene Expression Regulation, Leukemic / drug effects*
  • Gene Expression Regulation, Leukemic / genetics
  • Gene Rearrangement / drug effects
  • Gene Rearrangement / genetics
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Mice
  • Proto-Oncogene Proteins / drug effects*
  • Proto-Oncogene Proteins / genetics
  • Transcription Factors / drug effects
  • Transcription Factors / genetics


  • Chromatin
  • MEN1 protein, human
  • Proto-Oncogene Proteins
  • Transcription Factors