Proteasome inhibitors evoke latent tumor suppression programs in Pro-B MLL Leukemias through MLL-AF4 Journal Article
| Authors: | Liu, H.; Westergard, T. D.; Cashen, A.; Piwnica-Worms, D. R.; Kunkle, L.; Vij, R.; Pham, C. G.; DiPersio, J.; Cheng, E. H.; Hsieh, J. J. |
| Article Title: | Proteasome inhibitors evoke latent tumor suppression programs in Pro-B MLL Leukemias through MLL-AF4 |
| 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. © 2014 Elsevier Inc. |
| Journal Title: | Cancer Cell |
| Volume: | 25 |
| Issue: | 4 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2014-04-14 |
| Start Page: | 530 |
| End Page: | 542 |
| Language: | English |
| DOI: | 10.1016/j.ccr.2014.03.008 |
| PROVIDER: | scopus |
| PUBMED: | 24735925 |
| PMCID: | PMC4097146 |
| DOI/URL: | |
| Notes: | Cited By (since 1996):1 -- Export Date: 1 May 2014 -- CODEN: CCAEC -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work