Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 02 2023
13 02 2023
Historique:
received:
29
11
2021
accepted:
26
01
2023
entrez:
13
2
2023
pubmed:
14
2
2023
medline:
16
2
2023
Statut:
epublish
Résumé
Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsed/refractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.
Identifiants
pubmed: 36781850
doi: 10.1038/s41467-023-36370-x
pii: 10.1038/s41467-023-36370-x
pmc: PMC9925443
doi:
Substances chimiques
Proteasome Endopeptidase Complex
EC 3.4.25.1
Lysine
K3Z4F929H6
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
809Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2023. The Author(s).
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