| RRC ID |
79144
|
| 著者 |
Nakao F, Setoguchi K, Semba Y, Yamauchi T, Nogami J, Sasaki K, Imanaga H, Terasaki T, Miyazaki M, Hirabayashi S, Miyawaki K, Kikushige Y, Masuda T, Akashi K, Maeda T.
|
| タイトル |
Targeting a mitochondrial E3 ubiquitin ligase complex to overcome AML cell-intrinsic Venetoclax resistance.
|
| ジャーナル |
Leukemia
|
| Abstract |
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.
|
| 巻・号 |
37(5)
|
| ページ |
1028-1038
|
| 公開日 |
2023-5-1
|
| DOI |
10.1038/s41375-023-01879-z
|
| PII |
10.1038/s41375-023-01879-z
|
| PMID |
36973350
|
| MeSH |
Apoptosis Regulatory Proteins / metabolism
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Cell Line, Tumor
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / metabolism
Myeloid Cell Leukemia Sequence 1 Protein / genetics
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
Proto-Oncogene Proteins c-bcl-2* / genetics
Proto-Oncogene Proteins c-bcl-2* / metabolism
Ubiquitin-Conjugating Enzymes
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
bcl-2-Associated X Protein / genetics
|
| リソース情報 |
| 遺伝子材料 |
CSII-EF-MCS-IRES2-hKO1 (RDB07915)
pCAG-HIVgp (RDB04394)
pCMV-VSV-G-RSV-Rev (RDB04393) |
