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

Abstract

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.

• Authors: Andrei V Krivtsov, Kathryn Evans, Jayant Y Gadrey, Benjamin K Eschle, Charlie Hatton, Hannah J Uckelmann, Kenneth N Ross, Florian Perner, Sarah N Olsen, Tara Pritchard, Lisa McDermott, Connor D Jones, Duohui Jing, Ali Braytee, Diego Chacon, Eric Earley, Brian M McKeever, David Claremon, Andrew J Gifford, Heather J Lee, Beverly A Teicher, John E Pimanda, Dominik Beck, Jennifer A Perry, Malcolm A Smith, Gerard M McGeehan, Richard B Lock, Scott A Armstrong
• Journal: Cancer cell (Cancer Cell) Vol. 36 Issue 6 Pg. 660-673.e11 (12 09 2019) ISSN: 1878-3686 [Electronic] United States
• PMID: 31821784 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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