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

Autor:	Liu H; 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., Westergard TD; Department of Medicine, Washington University, St. Louis, MO 63105, USA., Cashen A; Department of Medicine, Washington University, St. Louis, MO 63105, USA., Piwnica-Worms DR; BRIGHT Institute, Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63105, USA., Kunkle L; Pharmacyclics, Sunnyvale, CA 94085, USA., Vij R; Department of Medicine, Washington University, St. Louis, MO 63105, USA., Pham CG; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., DiPersio J; Department of Medicine, Washington University, St. Louis, MO 63105, USA., Cheng EH; 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., Hsieh JJ; 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.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2014 Apr 14; Vol. 25 (4), pp. 530-42.
DOI:	10.1016/j.ccr.2014.03.008
Abstrakt:	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. (Copyright © 2014 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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