Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Apoptosis
/ drug effects
Cell Line, Tumor
Coculture Techniques
Drug Synergism
Gene Expression Regulation, Leukemic
/ drug effects
Histone-Lysine N-Methyltransferase
/ antagonists & inhibitors
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Mice
Mice, Inbred NOD
Myeloid Ecotropic Viral Integration Site 1 Protein
/ biosynthesis
Myeloid-Lymphoid Leukemia Protein
/ antagonists & inhibitors
Neoplasm Proteins
/ antagonists & inhibitors
Nuclear Proteins
/ genetics
Nucleophosmin
Phosphorylation
Protein Kinase Inhibitors
/ pharmacology
Protein Processing, Post-Translational
Proto-Oncogene Proteins
/ antagonists & inhibitors
Random Allocation
Transcription, Genetic
/ drug effects
fms-Like Tyrosine Kinase 3
/ antagonists & inhibitors
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
19 11 2020
19 11 2020
Historique:
received:
24
01
2020
accepted:
11
06
2020
pubmed:
27
6
2020
medline:
7
4
2021
entrez:
27
6
2020
Statut:
ppublish
Résumé
The interaction of menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and provides a potential opportunity for treatment of NPM1-mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. In this study, transcriptional profiling after pharmacological inhibition of the menin-MLL complex revealed specific changes in gene expression, with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being the most pronounced. Combining menin-MLL inhibition with specific small-molecule kinase inhibitors of FLT3 phosphorylation resulted in a significantly superior reduction of phosphorylated FLT3 and transcriptional suppression of genes downstream of FLT3 signaling. The drug combination induced synergistic inhibition of proliferation, as well as enhanced apoptosis, compared with single-drug treatment in models of human and murine NPM1mut and MLL-r leukemias harboring an FLT3 mutation. Primary acute myeloid leukemia (AML) cells harvested from patients with NPM1mutFLT3mut AML showed significantly better responses to combined menin and FLT3 inhibition than to single-drug or vehicle control treatment, whereas AML cells with wild-type NPM1, MLL, and FLT3 were not affected by either of the 2 drugs. In vivo treatment of leukemic animals with MLL-r FLT3mut leukemia reduced leukemia burden significantly and prolonged survival compared with results in the single-drug and vehicle control groups. Our data suggest that combined menin-MLL and FLT3 inhibition represents a novel and promising therapeutic strategy for patients with NPM1mut or MLL-r leukemia and concurrent FLT3 mutation.
Identifiants
pubmed: 32589720
pii: S0006-4971(20)82002-3
doi: 10.1182/blood.2020005037
pmc: PMC8215191
doi:
Substances chimiques
KMT2A protein, human
0
MEIS1 protein, human
0
MEN1 protein, human
0
Meis1 protein, mouse
0
Men1 protein, mouse
0
Myeloid Ecotropic Viral Integration Site 1 Protein
0
NPM1 protein, human
0
Neoplasm Proteins
0
Npm1 protein, mouse
0
Nuclear Proteins
0
Protein Kinase Inhibitors
0
Proto-Oncogene Proteins
0
Nucleophosmin
117896-08-9
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2442-2456Subventions
Organisme : Medical Research Council
ID : MC_PC_17230
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P50 CA206963
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA197498
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA233691
Pays : United States
Organisme : Medical Research Council
ID : MC_PC_12009
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA236626
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 by The American Society of Hematology.
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