Targeting a mitochondrial E3 ubiquitin ligase complex to overcome AML cell-intrinsic Venetoclax resistance.
Humans
Myeloid Cell Leukemia Sequence 1 Protein
/ genetics
Cell Line, Tumor
bcl-2-Associated X Protein
/ genetics
Proto-Oncogene Proteins c-bcl-2
/ genetics
Bridged Bicyclo Compounds, Heterocyclic
/ pharmacology
Ubiquitin-Protein Ligases
/ genetics
Apoptosis Regulatory Proteins
/ metabolism
Leukemia, Myeloid, Acute
/ drug therapy
Ubiquitin-Conjugating Enzymes
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
received:
11
10
2022
accepted:
16
03
2023
revised:
09
03
2023
medline:
11
5
2023
pubmed:
28
3
2023
entrez:
27
3
2023
Statut:
ppublish
Résumé
To identify molecules/pathways governing Venetoclax (VEN) sensitivity, we performed genome-wide CRISPR/Cas9 screens using a mouse AML line insensitive to VEN-induced mitochondrial apoptosis. Levels of sgRNAs targeting March5, Ube2j2 or Ube2k significantly decreased upon VEN treatment, suggesting synthetic lethal interaction. Depletion of either Ube2j2 or Ube2k sensitized AML cells to VEN only in the presence of March5, suggesting coordinate function of the E2s Ube2j2 and Ube2k with the E3 ligase March5. We next performed CRISPR screens using March5 knockout cells and identified Noxa as a key March5 substrate. Mechanistically, Bax released from Bcl2 upon VEN treatment was entrapped by Mcl1 and Bcl-XL and failed to induce apoptosis in March5 intact AML cells. By contrast, in March5 knockout cells, liberated Bax did not bind to Mcl1, as Noxa likely occupied Mcl1 BH3-binding grooves and efficiently induced mitochondrial apoptosis. We reveal molecular mechanisms underlying AML cell-intrinsic VEN resistance and suggest a novel means to sensitize AML cells to VEN.
Identifiants
pubmed: 36973350
doi: 10.1038/s41375-023-01879-z
pii: 10.1038/s41375-023-01879-z
doi:
Substances chimiques
Myeloid Cell Leukemia Sequence 1 Protein
0
venetoclax
N54AIC43PW
bcl-2-Associated X Protein
0
Proto-Oncogene Proteins c-bcl-2
0
Bridged Bicyclo Compounds, Heterocyclic
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Apoptosis Regulatory Proteins
0
UBE2K protein, human
EC 2.3.2.23
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
UBE2J2 protein, human
EC 2.3.2.23
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1028-1038Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
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