Proteasome inhibitors evoke latent tumor suppression programs in Pro-B MLL Leukemias through MLL-AF4

Han Liu, Todd D. Westergard, Amanda Cashen, David R. Piwnica-Worms, Lori Kunkle, Ravi Vij, Can G. Pham, John DiPersio, Emily H. Cheng, James J. Hsieh

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


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.

Original languageEnglish
Pages (from-to)530-542
Number of pages13
JournalCancer Cell
Issue number4
StatePublished - Apr 14 2014


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