Proteasome inhibition drastically but reversibly impairs murine lymphocyte development.
The proteasome inhibitor bortezomib, which induces cell death in various cancer cell lines including lymphatic neoplasias, has recently been approved for the treatment of relapsed multiple myeloma. Important mechanisms of proteasome inhibitor-mediated tumor cell death are the inhibition of NF-kappaB activation and induction of the terminal unfolded protein response (UPR). However, little is known about effects of bortezomib on developing and mature lymphocytes. Therefore, Balb/C mice were injected with bortezomib and lymphocyte subsets were analyzed. This treatment resulted in dramatically decreased numbers of T and B lymphocyte precursors, while mature lymphocytes were only partially affected. Thymocytes were almost depleted 3 days after a single bortezomib injection, pro-B and pre-B cells already after 2 days. Thymocytes and B cell precursors recovered within 2 weeks. The decreased numbers of developing lymphocytes were due to apoptotic cell death accompanied by strongly increased caspase 3/7 activity. Within 8 h after bortezomib injection, there was a strong induction of heat shock protein 70 and C/EBP homologous protein in bone marrow B cells, indicating endoplasmic reticulum stress and activation of the terminal UPR, respectively. Hence, induction of apoptosis by proteasome inhibition can dramatically affect lymphocyte development, a fact which has important implications for the clinical use of bortezomib, especially in situations with ongoing lymphopoiesis.
Maseda
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D
IZKF Junior Research Group N2, Nikolaus-Fiebiger-Center of Molecular Medicine, University Hospital Erlangen, Erlangen, Germany.
Meister
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S
Neubert
K
K
Herrmann
M
M
Voll
R E
RE
D000818:Animals; D017209:Apoptosis; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002478:Cells, Cultured; D005260:Female; D018655:Lymphocyte Count; D008221:Lymphoid Tissue / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000187:drug effects*; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D017510:Protein Folding; D011719:Pyrazines / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib