A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia.
Animals
Apoptosis
/ drug effects
Cell Differentiation
/ drug effects
Cell Proliferation
/ drug effects
Chromatin
/ drug effects
Gene Expression Regulation, Leukemic
/ drug effects
Gene Rearrangement
/ drug effects
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Mice
Proto-Oncogene Proteins
/ drug effects
Transcription Factors
/ drug effects
DOT1L
MLL fusion
Menin inhibitor
acute myeloid leukemia (AML)
chromatin remodeling
infant B cell acute lymphoblastic leukemia (B-ALL)
leukemia
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
09 12 2019
09 12 2019
Historique:
received:
15
03
2019
revised:
23
09
2019
accepted:
04
11
2019
entrez:
11
12
2019
pubmed:
11
12
2019
medline:
28
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31821784
pii: S1535-6108(19)30521-5
doi: 10.1016/j.ccell.2019.11.001
pmc: PMC7227117
mid: NIHMS1545811
pii:
doi:
Substances chimiques
Chromatin
0
MEN1 protein, human
0
Proto-Oncogene Proteins
0
Transcription Factors
0
Types de publication
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.
Langues
eng
Sous-ensembles de citation
IM
Pagination
660-673.e11Subventions
Organisme : NCI NIH HHS
ID : U01 CA199000
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA206963
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA199222
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA176745
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204639
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA066996
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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