Proteasome inhibitors evoke latent tumor suppression programs in pro-B MLL leukemias through MLL-AF4.
Cancer Cell
; 25(4): 530-42, 2014 Apr 14.
Article
in En
| MEDLINE
| ID: mdl-24735925
ABSTRACT
Chromosomal translocations disrupting MLL generate MLL-fusion proteins that induce aggressive leukemias. Unexpectedly, MLL-fusion proteins are rarely observed at high levels, suggesting excessive MLL-fusions may be incompatible with a malignant phenotype. Here, we used clinical proteasome inhibitors, bortezomib and carfilzomib, to reduce the turnover of endogenous MLL-fusions and discovered that accumulated MLL-fusions induce latent, context-dependent tumor suppression programs. Specifically, in MLL pro-B lymphoid, but not myeloid, leukemias, proteasome inhibition triggers apoptosis and cell cycle arrest involving activation cleavage of BID by caspase-8 and upregulation of p27, respectively. Furthermore, proteasome inhibition conferred preliminary benefit to patients with MLL-AF4 leukemia. Hence, feasible strategies to treat cancer-type and oncogene-specific cancers can be improvised through harnessing inherent tumor suppression properties of individual oncogenic fusions.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oncogene Proteins, Fusion
/
Myeloid-Lymphoid Leukemia Protein
/
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/
Proteasome Inhibitors
Limits:
Adult
/
Animals
/
Humans
Language:
En
Journal:
Cancer Cell
Journal subject:
NEOPLASIAS
Year:
2014
Document type:
Article
Affiliation country:
China