Receptor Expressed in Lymphoid Tissues (RELT) is a human tumor necrosis factor receptor superfamily member (TNFRSF) that is expressed most prominently in cells and tissues of the hematopoietic system. RELL1 and RELL2 are two homologs that physically interact with RELT and co-localize with RELT at the plasma membrane. This study sought to further elucidate the function of RELT by identifying novel protein interactions with RELT family members. The transcription factor MyoD family inhibitor domain-containing (MDFIC) was identified in a yeast two-hybrid genetic screen using RELL1 as bait. MDFIC co-localizes with RELT family members at the plasma membrane; this co-localization was most prominently observed with RELL1 and RELL2. In vitro co-immunoprecipitation (Co-IP) was utilized to demonstrate that MDFIC physically interacts with RELT, RELL1, and RELL2. Co-IP using deletion mutants of MDFIC and RELT identified regions important for physical association between MDFIC and RELT family members and a computational analysis revealed that RELT family members are highly disordered proteins. Immunohistochemistry of normal human lymph nodes revealed RELT staining that was most prominent in macrophages. Interestingly, the level of RELT staining significantly increased progressively in low and high-grade B-cell lymphomas versus normal lymph nodes. RELT co-staining with CD20 was observed in B-cell lymphomas, indicating that RELT is expressed in malignant B cells. Collectively, these results further our understanding of RELT-associated signaling pathways, the protein structure of RELT family members, and provide preliminary evidence indicating an association of RELT with B-cell lymphomas.

In this chapter, the authors will discuss the epidemiology and clinical presentations of amyloidosis. The main body of this chapter will concentrate on treatment options, both FDA-approved and experimental, specific to the various forms of amyloidosis. Since this set of diseases can affect multiple organ systems, we tackle the therapeutic avenues and the current challenges in each system under clinical investigation, including neurological, psychiatric, gastrointestinal, cardiovascular, endocrine, renal and hematologic, in addition to options for palliative treatment for severe symptom management and improved quality of life. Several recent groundbreaking discoveries have opened up the potential for successful treatment of peripheral and central neurological amyloidoses making this an exciting and evolving field.

Receptor Expressed in Lymphoid Tissues (RELT) is a human TNFR that is expressed prominently in the hematopoietic system and negatively regulates T-cell activation in mice. RELT has two identified homologous binding partners, RELL1 and RELL2. This study sought to further elucidate the function of RELT by identifying novel protein interactions with RELT family members and to study the localization of RELT in both normal and diseased tissues. A yeast two-hybrid screen identifed Phospholipid Scramblase 1 (PLSCR1) and MyoD family inhibitor domain-containing protein (MDFIC) as potential RELT-family member binding proteins that were confirmed by in vitro co-immunoprecipitations. PLSCR1 has been demonstrated to possess anti-leukemic properties, and RELT expression results in an altered cellular localization of PLSCR1 as determined by immunofluorescence (IF). The MDFIC gene encodes for a transcription factor and is located proximally to regions of chromosome 7 (7q31.1) frequently lost in AML patients. MDFIC was observed to co-localize with RELL1 at the plasma membrane and co-localize with RELT in intracellular compartments as determined by IF. Since RELT, PLSCR1 and MDFIC are prominently expressed in the hematopoietic system, we sought to characterize the expression of RELT in both normal lymph nodes and B cell lymphomas. Immunohistochemistry revealed a higher intensity of RELT staining in germinal centers in comparison to surrounding lymph node regions. Interestingly, the level of RELT staining increased progressively in low and high-grade B cell lymphomas versus normal lymph nodes. Collectively, these results further our understanding of proteins that interact with RELT and identify an association of RELT with B cell lymphomas.

Receptor Expressed in Lymphoid Tissues (RELT) is a human TNFR superfamily member expressed most prominently in cells and tissues of the hematopoietic system. Mouse knockout studies indicate that RELT functions in part by negatively regulating T-cell activation. RELT has two homologous binding partners, RELL1 and RELL2, and collectively, these proteins are described as RELT family members. This study sought to identify novel protein interactions with RELT family members and to compare the expression of RELT in normal and diseased tissues. A yeast two-hybrid screen utilizing RELL1 as bait identified the cytoskeletal protein Filamin A (FlnA); physical interaction between FlnA and RELT family members was confirmed by in vitro co-immunoprecipitation. A truncated mutant of FlnA disrupts the ability of RELT family members to activate the p38 pathway. Previous reports indicate that autoantibodies against RELT are associated with breast cancer and that RELL2 prevents migration and invasion of the metastatic breast cancer cell line MDA-MB-231 (231), while multiple studies suggest a link between FlnA and breast cancer. We therefore sought to examine the association of RELT family members with breast cancer. Western blotting revealed significant expression of endogenous RELT family members in the breast cancer cell lines 231 and MCF-7. Immunohistochemistry (IHC) revealed a higher intensity of RELT staining in breast cancer tissues versus normal mammary tissue. Additionally, overexpression of RELT family members enhanced apoptosis in 231 cells. Collectively, these results further our understanding of signal transduction pathways associated with RELT family members and provide evidence that RELT is upregulated in breast cancer.