Anti-SEL1L (aa 300-400) polyclonal antibody

Systemic AL amyloidosis is a clonal plasma cell disease in which the clonal cells in the marrow of more than half of patients express high levels of cyclin D1. We studied these cells from 69 patients at diagnosis and show that protein quality control gene expression, monoclonal immunoglobulin secretion, response to therapy and overall survival vary based on cyclin D1 levels. Background: Overexpression of cyclin D1 (CCND1) in the clonal plasma cells (PCs) of patients with systemic light chain amyloidosis (AL) has been shown to occur even in cases without t(11;14). Associations between CCND1 expression and the clonal PC disease that underlies AL and the clinical features that characterize AL have not been systematically evaluated. Patients and Methods: To assess the significance of CCND1 expression in the pathophysiology of the clonal PC in AL, we evaluated CD138+ marrow PC from 16 newly diagnosed untreated patients by gene expression profiling (GEP) and performed a supervised analysis comparing clones that overexpressed CCND1 with those that did not. To assess the significance of CCND1 expression with respect to the clinical features of AL, we developed and validated a real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) method for quantitating expression of CCND1 in the CD138+ marrow PC cells from 53 newly diagnosed cases of AL. Results: In the analysis of GEP data, clones that overexpressed CCND1 also expressed significantly higher levels of endoplasmic reticulum protein processing genes such as SEL1L, Sec63, and PD1A6. In the analysis of RT-qPCR data, patients whose clones overexpressed CCND1 more often made only free light chains and fewer intact M-proteins, and also had a lower response rate to initial therapy. In multivariate analysis, CCND1 expression was an independent baseline predictor of survival in AL. Conclusion: CCND1 expression is a feature of the clonal PC disease in AL that merits prospective evaluation.

Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfold protein response (UPR) and ER-associated degradation (ERAD) are the primary ER quality control mechanism. The adaptor protein Sel1L (Suppressor/Enhancer of Lin-12-like) controls the stability of the E3 ubiquitin ligase Hrd1 (hydroxymethylglutaryl reductase degradation protein 1), and is necessary for the ERAD activity of the Sel1L-Hrd1 complex. Herein, we showed that Sel1L deficiency specifically in oligodendrocytes caused ERAD impairment, the UPR activation, and attenuation of myelin protein biosynthesis; and resulted in late-onset, progressive myelin thinning in the CNS of adult mice (both male and female). The pancreatic ER kinase (PERK) branch of the UPR functions as the master regulator of protein translation in ER-stressed cells. Importantly, PERK inactivation reversed attenuation of myelin protein biosynthesis in oligodendrocytes and restored myelin thickness in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). Conversely, blockage of proteolipid protein production exacerbated myelin thinning in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). These findings suggest that impaired ERAD in oligodendrocytes reduces myelin thickness in the adult CNS through suppression of myelin protein translation by activating PERK.