The deubiquitinase USP15 modulates cellular redox and is a therapeutic target in acute myeloid leukemia.
Animals
Apoptosis
Cell Proliferation
Female
Humans
Kelch-Like ECH-Associated Protein 1
/ genetics
Leukemia, Myeloid, Acute
/ genetics
Male
Mice
Mice, Inbred C57BL
NF-E2-Related Factor 2
/ genetics
Oxidation-Reduction
Oxidative Stress
Prognosis
Signal Transduction
Tumor Cells, Cultured
Ubiquitin-Specific Proteases
/ genetics
Xenograft Model Antitumor Assays
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
12
03
2021
accepted:
19
08
2021
revised:
17
08
2021
pubmed:
2
9
2021
medline:
16
2
2022
entrez:
1
9
2021
Statut:
ppublish
Résumé
Ubiquitin-specific peptidase 15 (USP15) is a deubiquitinating enzyme implicated in critical cellular and oncogenic processes. We report that USP15 mRNA and protein are overexpressed in human acute myeloid leukemia (AML) as compared to normal hematopoietic progenitor cells. This high expression of USP15 in AML correlates with KEAP1 protein and suppression of NRF2. Knockdown or deletion of USP15 in human and mouse AML models significantly impairs leukemic progenitor function and viability and de-represses an antioxidant response through the KEAP1-NRF2 axis. Inhibition of USP15 and subsequent activation of NRF2 leads to redox perturbations in AML cells, coincident with impaired leukemic cell function. In contrast, USP15 is dispensable for human and mouse normal hematopoietic cells in vitro and in vivo. A preclinical small-molecule inhibitor of USP15 induced the KEAP1-NRF2 axis and impaired AML cell function, suggesting that targeting USP15 catalytic function can suppress AML. Based on these findings, we report that USP15 drives AML cell function, in part, by suppressing a critical oxidative stress sensor mechanism and permitting an aberrant redox state. Furthermore, we postulate that inhibition of USP15 activity with small molecule inhibitors will selectively impair leukemic progenitor cells by re-engaging homeostatic redox responses while sparing normal hematopoiesis.
Identifiants
pubmed: 34465865
doi: 10.1038/s41375-021-01394-z
pii: 10.1038/s41375-021-01394-z
pmc: PMC8807387
doi:
Substances chimiques
KEAP1 protein, human
0
Kelch-Like ECH-Associated Protein 1
0
NF-E2-Related Factor 2
0
USP15 protein, human
EC 3.4.19.12
Ubiquitin-Specific Proteases
EC 3.4.19.12
Usp15 protein, mouse
EC 3.4.19.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
438-451Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK102759
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL135787
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211404
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK113639
Pays : United States
Organisme : NCI NIH HHS
ID : K00 CA234924
Pays : United States
Informations de copyright
© 2021. The Author(s).
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