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The activity of NF-?B/Rel transcription factors can downmodulate apoptosis in normal and neoplastic cells of the hematologic and other compartments, contributing in maintaining neoplastic clone survival and impairing response to therapy. Alterations in nf?b or i?B genes are documented in some hematologic neoplasias, while in others dysfunction in NF-?B/Rel-activating signaling pathways can be recognized. The prosurvival properties of NF-?B/Rel appear to rely on the induced expression of molecules (caspase inhibitors, Bcl2 protein family members, etc.), which interfere with the apoptosis pathway. Constitutive NF-?B/Rel activity in some hematologic malignancies could be advantageous for neoplastic clone expansion by counteracting stress stimuli (consumption of growth factors and metabolites) and immune system-triggered apoptosis; it is furthermore likely to play a central role in determining resistance to therapy. Based on this evidence, NF-?B/Rel-blocking approaches have been introduced in antineoplastic strategies. The identification of NF-?B/Rel target genes relevant for survival in specific neoplasias is required in order to address tailored therapies and avoid possible detrimental effects due to widespread NF-?B/Rel inhibition. Moreover, comparative analyses of normal hematopoietic progenitors and neoplastic cell sensitivities to inhibitors of NF-?B/Rel and their target genes will allow to evaluate the impact of these tools on normal bone marrow.Leukemia (2004) 18, 11-17. doi:10.1038/sj.leu.2403171 Published online 23 October 2003 [ABSTRACT FROM AUTHOR]

The present study was designed to determine the molecular mechanisms by which interleukin (IL)-10 prevents the HLA class I antigen expression at the cell surface. In this context, the potential role of transporter associated with antigen presentation 1+2 (TAP1+2) molecules and NF-κB transcription factors was addressed. The IL-10 effect was investi-gated in a human lymphoblastoid cell system defective for TAP1+2 genes (T2 cell line) and in the related TAP1+2 transfectants (T3 cell line). In this experimental system, after 48 h of incubation in the presence of IL-10, the HLA class I antigen downmodulation was observed in the T3 but not in the T2 cell line, suggesting a potential role of TAP1+2 molecules. In the same experimental conditions, the NF-κB activity was unaffected. Instead, after 3 h of exposuretoIL-10, the HLA downmodulation was observed in both cell lines, the NF-κB factors activity being strongly reduced. In addition, the transfection of the inhibitor of NF-κB, IκBa, prevented the IL-10 effect on HLA class I antigen expression in the T3 cell line. This phenomenon was observed after 3 h but not 48 h of IL-10 incubation. These evidences indicate a time dependent involvement of TAP1+2 antigens and of NF-κB activity in the IL-10-induced major histocompatibility complex (MHC) class I downmodulation. [ABSTRACT FROM AUTHOR]

Indicates that stress-induced apoptosis in normal and neoplastic leukocytes is regulated by BAG3 protein. Characteristics of BAG3; Influence of BAG3 levels on the apoptotic response of human leukocytes to oxidative stress; Effect of the modulation of BAG3 protein levels on basal cell survival.