title: Bortezomib sensitivity of acute myeloid leukemia CD34(+) cells can be enhanced by targeting the persisting activity of NF-κB and the accumulation of MCL-1.
abstract: Sustained NF-κB activation is often observed in acute myeloid leukemia (AML); therefore, proteasome inhibition has been proposed to efficiently target AML cells. In this study, we questioned whether leukemic stem cell-enriched CD34(+) cells are sensitive to the proteasome inhibitor bortezomib. Surprisingly, we observed in short-term and long-term culture assays that CD34(-) AML cells were more sensitive to bortezomib treatment compared with the CD34(+) AML cells at a clinical relevant dosage. Cotreatment with the apoptosis-inducing cytokine TRAIL did not enhance cell death in CD34(+) AML cells, in contrast to the effects in AML cell lines. The better survival of CD34(+) AML cells upon bortezomib treatment was due to a persisting NF-κB activity that could be overcome by the IKK inhibitor BMS-345541. This difference in sensitivity might be related to differences in NF-κB activation in AML CD34(+) versus CD34(-) cells, as suggested by a gene expression profiling study. Besides NF-κB, MCL-1 strongly determines the effectiveness of bortezomib. MCL-1 accumulated in CD34(+) AML cells upon bortezomib treatment and inhibition of MCL-1 by shRNA, or Obatoclax, significantly improved the sensitivity of CD34(+) AML cells to bortezomib. These results demonstrate that combining bortezomib with specific NF-κB or MCL-1 inhibitors might potentially target the leukemic stem cells.
authors: Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors: Matthieu Cornelis Johannes
authors: MC
authors: Bosman
authors: Jan Jacob
authors: JJ
authors: Schuringa
authors: Wilhelmus Johannes
authors: WJ
authors: Quax
authors: Edo
authors: E
authors: Vellenga
mesh_terms: D018952:Antigens, CD34 / Q000032:analysis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D007093:Imidazoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D061251:Primary Cell Culture / Q000379:methods; D011480:Protease Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D017154:Stromal Cells / Q000166:cytology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D018952:Antigens, CD34; D001897:Boronic Acids; D007093:Imidazoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D011810:Quinoxalines; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000069286:Bortezomib; C496559:CHUK protein, human; D051550:I-kappa B Kinase