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Cancer Cell. 2014 Apr 14;25(4):530-42. doi: 10.1016/j.ccr.2014.03.008.

Proteasome inhibitors evoke latent tumor suppression programs in pro-B MLL leukemias through MLL-AF4.

Author information

1
Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
2
Department of Medicine, Washington University, St. Louis, MO 63105, USA.
3
BRIGHT Institute, Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63105, USA.
4
Pharmacyclics, Sunnyvale, CA 94085, USA.
5
Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: chenge1@mskcc.org.
7
Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: hsiehj@mskcc.org.

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.

PMID:
24735925
PMCID:
PMC4097146
DOI:
10.1016/j.ccr.2014.03.008
[Indexed for MEDLINE]
Free PMC Article

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