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

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

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA.
2
Children's Cancer Institute, School of Women's and Children's Health, UNSW, Sydney 2052, Australia.
3
Lowy Cancer Research Centre and the Prince of Wales Clinical School, UNSW, Sydney 2052, Australia; Centre for Health Technologies and the School of Biomedical Engineering, University of Technology Sydney, Ultimo, NSW 2007, Australia.
4
RTI International, Research Triangle Park, NC 27709, USA.
5
Brian Michael McKeever, LLC, Lake Ronkonkoma, NY 11779, USA.
6
CGM Pharma, LLC, Fort Washington, PA 19034, USA.
7
Children's Cancer Institute, School of Women's and Children's Health, UNSW, Sydney 2052, Australia; Department of Anatomical Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia.
8
School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW 2308, Australia.
9
National Cancer Institute, Bethesda, MD 20892, USA.
10
Lowy Cancer Research Centre and the Prince of Wales Clinical School, UNSW, Sydney 2052, Australia; Department of Haematology, Prince of Wales Hospital, Sydney, NSW 2210, Australia.
11
Syndax Pharmaceuticals, Waltham, MA 02451, USA.
12
Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA. Electronic address: scott_armstrong@dfci.harvard.edu.

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.

KEYWORDS:

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

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