HSP90 inhibition caused a small but statistically significant decrease of FLT3 CD135 levels . Additional independent experiments.The effect of the HSP90 inhibitor 17DMAG on cytokinedependent AML cell proliferation was examined. In the initial experiments we tested a broad concentration range for an initial cohort of 12 consecutive AML JAK-STAT Signaling Pathway patients; the drug then had an antiproliferative effect for all patients at concentrations exceeding 10 lmol l but individual patients differed in their susceptibility to HSP90 inhibition . Thereafter, we examined the effect of five selected concentrations over a smaller range for 52 additional unselected patients .
We could not detect any difference in the antiproliferative effect between the two major HSP expression clusters , the growthinhibitory effect Sunitinib was not correlated with the level of any single HSP and there was no correlation between the antiproliferative effect and any clinical or biological AML characteristics including FLT3 mutations . Finally, we also investigated the effect of 10 lmol l 17DMAG on clonogenic AML cell proliferation for a cohort of 16 unselected patients. The leukaemic cells were precultured for 7 d in suspension cultures with and without 17DMAG before analysis of clonogenic cells. 17DMAG caused a similar reduction in the number of clonogenic cells for all these unselected patients induces death of malignant plasma cells by activation of the unfolded protein response, a signaling pathway activated by accumulation of misfolded proteins within the endoplasmic reticulum.
We hypothesized that nontransformed plasma cells are also hypersensitive to Hsp90 inhibition because of their high amount of tissues protein biosynthesis. To investigate this hypothesis, 2 different Hsp90 inhibitors, the geldanamycin derivative 17DMAG and the nontoxic peptide derivative TCBL 145, were applied to mice with experimental epidermolysis bullosa acquisita, an autoimmune bullous disease characterized by autoantibodies against type VII collagen of the dermalepidermal junction. Both inhibitors ameliorated clinical disease of type VII collagen–immunized mice, suppressed autoantibody production, and reduced dermal neutrophilic infiltrate. Interestingly, total plasma cell numbers, type VII collagen–specific plasma cells, and germinal center B cells were unaffected by antiHsp90 treatment Autoreactive T cells, B cells, and plasma cells have been identified as key players in the pathophysiology of autoimmune diseases.
Although much progress has been made in revealing the immunologic processes in these diseases, their therapy remains challenging and in most cases still consists of conventional, unspecific immunosuppressive treatment with corticosteroids and cytostatic agents. However, the application of these drugs is often limited due to side effects, and disease remission frequently cannot be achieved.1 Epidermolysis bullosa acquisita is a chronic subepidermal blistering disease characterized by circulating and tissuebound autoantibodies targeting the noncollagenous domain 1 of type VII collagen, a major component of anchoring fibrils of the dermalepidermal junction.2,3 The pathogenic relevance of antibodies against type VII collagen has been conclusively shown ex vivo and in experimental .