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.
authors.affiliation: 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.
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medicine, Washington University, St. Louis, MO 63105, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Westergard
authors.affiliation: Department of Medicine, Washington University, St. Louis, MO 63105, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Cashen
authors.affiliation: BRIGHT Institute, Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63105, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Piwnica-Worms
authors.affiliation: Pharmacyclics, Sunnyvale, CA 94085, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Kunkle
authors.affiliation: Department of Medicine, Washington University, St. Louis, MO 63105, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vij
authors.affiliation: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Can G
authors.initials: CG
authors.lastname: Pham
authors.affiliation: Department of Medicine, Washington University, St. Louis, MO 63105, USA.
authors.forename: John
authors.initials: J
authors.lastname: DiPersio
authors.affiliation: 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.
authors.forename: Emily H
authors.initials: EH
authors.lastname: Cheng
authors.affiliation: 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.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hsieh
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D004268:DNA-Binding Proteins; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D035602:Transcriptional Elongation Factors; D014162:Transfection; D014178:Translocation, Genetic
chemical_list: D001897:Boronic Acids; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D061988:Proteasome Inhibitors; D011719:Pyrazines; D034741:RNA, Small Interfering; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D000069286:Bortezomib; D011495:Histone-Lysine N-Methyltransferase
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