In localized light chain amyloidosis (locAL), amyloidogenic light chains (aLC) are produced and deposited locally by a B‐cell clone. We present 293 patients with immunohistochemically confirmed locAL. Lung (nodular pulmonary) with 63 patients was the most involved organ. The aLC was λ in 217 cases (κ:λ ratio 1:3). A local B‐cell clone was identified in 30% of cases. Sixty‐one (21%) had a concomitant autoimmune disorder (cAD). A monoclonal component (MC) were present in 101 (34%) patients and were more frequent in subjects with cAD (51% vs 34%; P = .03). Cigarette smoking was more prevalent in lung locAL (54% vs 37%; P = .018). After a median follow‐up of 44 months, 16 patients died and 5‐ and 10‐years locAL progression‐free survival (PFS) were 62% and 44%. Interestingly, locAL‐PFS was shorter among patients with an identified clonal infiltrate at amyloid deposition site (40 vs 109 months; P = .02) and multinuclear giant cells and/or an inflammatory infiltrate resulted in longer locAL‐PFS in lung involvement (65 vs 42 months; P = .01). However, no differences in locAL PFS were observed in patients with cAD, a MC and involved organ site. Treatment was administered in 163 (54%) patients and was surgical in 135 (46%). Median locAL‐PFS after first treatment was 56 months. Responders had longer locAL‐PFS (78 vs 17 months; P < .001). Three patients with lung locAL and a MC were diagnosed as systemic AL amyloidosis at follow‐up. In summary, locAL pathogenesis seems to be heterogeneous and the clonal infiltrate leads local progression.
The mode of activation of glycoprotein 130 kDa (gp130) and the transmission of the activation status through the plasma membrane are incompletely understood. In particular, the molecular function of the three juxtamembrane fibronectin III-like domains of gp130 in signal transmission remains unclear. To ask whether forced dimerization of gp130 is sufficient for receptor activation, we replaced the entire extracellular portion of gp130 with the c-jun leucine zipper region in the chimeric receptor protein L-gp130. On expression in cells, L-gp130 stimulates ligand-independent signal transducer and activator of transcription (STAT) 3 and extracellular signal-regulated kinase 1/2 phosphorylation. gp130 activation could be abrogated by the addition of a competing peptide comprising the leucine zipper region of c-fos. When stably expressed in the interleukin-3-dependent Ba/F3 murine pre-B-cells, these cells showed constitutive STAT3 activation and cytokine-independent growth over several months. Because gp130 stimulation completely suppressed differentiation of murine embryonic stem cells in vitro, we also stably expressed L-gp130 in these cells, which completely blocked their differentiation in the absence of cytokine stimulation and was consistent with high constitutive expression levels of the stem cell factor OCT-4. Thus, L-gp130 can be used in vitro and in vivo to mimic constitutive and ligand-independent activation of gp130 and STAT3, the latter of which is frequently observed in neoplastic diseases. INTRODUCTIONThe interleukin (IL)-6 family of cytokines consists of IL-6, IL-11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), Oncostatin M (OSM), IL-27, and new neurotrophin-1 (NNT-1). IL-6 and IL-11 induce the formation of a glycoprotein 130 kDa (gp130)-homodimer, whereas signaling by LIF, CNTF, CT-1, and NNT-1 results in the formation of a gp130/leukemia inhibitory factor receptor (LIFR) heterodimer. OSM can induce the formation of a dimer of gp130 with LIFR and the related protein OSMR (Taga and Kishimoto, 1997). IL-27 exclusively signals via a heterodimer composed of gp130 and the WSX-1 receptor (Pflanz et al., 2004).IL-6 has pro-and anti-inflammatory properties and plays a central role in host defense against infection and tissue injuries (Simpson et al., 1997). The activities of IL-6 are highly pleiotropic, stimulating a wide range of biological activities, including B-cell maturation, hepatocyte regeneration, and neuronal growth .IL-6 binds to the specific IL-6 receptor (IL-6R), and this complex associates with two molecules of the ubiquitously expressed gp130 Heinrich et al., 2003). The formation of a hetero-oligomeric receptor complex containing the gp130 signal transducing receptor leads to intracellular activation of Janus tyrosine kinase (JAK)/ Tyk tyrosine kinases as well as the signal transducer and activator of transcription (STAT) family of transcription factors. Furthermore, gp130 activation leads to stimulation of the phosphoinositide 3-kinase and RAS/mitogen-activated protein...
Approximately 15% of follicular lymphomas (FLs) lack breaks in the BCL2 locus. The aim of this study was to better define molecular and clinical features of BCL2-breakpoint/t(14;18)-negative FLs. We studied the presence of BCL2, BCL6 and MYC breaks by fluorescence in situ hybridization and the expression of BCL2, MUM1, CD10, P53 and Ki67 in large clinical trial cohorts of 540 advanced-stage FL cases and 116 early-stage disease FL patients treated with chemotherapy regimens and radiation, respectively. A total of 86% and 53% of advanced- and early-stage FLs were BCL2-breakpoint-positive, respectively. BCL2 was expressed in almost all FLs with BCL2 break and also in 86% and 69% of BCL2-breakpoint-negative advanced- and early-stage FLs, respectively. CD10 expression was significantly reduced in BCL2-breakpoint-negative FLs of all stages and MUM1 and Ki67 expression were significantly increased in BCL2-break-negative early-stage FLs. Patient characteristics did not differ between FLs with and without BCL2 breaks and neither did survival times in advanced-stage FLs. These results suggest that the molecular profile differs to some extent between FLs with and without BCL2 breaks and support the notion that FLs with and without BCL2 breaks belong to the same lymphoma entity.
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