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Monoclonal gammopathy of renal significance (MGRS) is a new nosological group of entities (meta-entity) defined in 2012, whose pathogenesis depends on monoclonal immunoglobulins (Ig) secreted by low-grade lymphoproliferative disorders, which belong to M-protein-related diseases. Renal damage is the result of monoclonal Ig deposit or its activity as autoantibodies, which can compromise any nephronal area. MGRS does not include kidney diseases produced by high-grade lymphoproliferative disorders as well as those whose pathogenesis are independent of monoclonal Ig (such as drug toxicity or metabolic disorders). The importance of this hemato-nephrological meta-entity is based on two aspects: First, it is associated with increased morbidity and mortality, including recurrence in post-renal transplant or its appearance as "de novo" after it; and second, it usually improves after treating the plasmocyte or lymphocyte clone responsible, leading to the elimination of M-protein. Between low-grade lymphoproliferative disorders, monoclonal gammopathy of undetermined significance (MGUS) requires special consideration for two reasons: First, it is the disorder most related to MGRS; second, when MGUS progresses to MGRS, effective treatment against toxic underline clone should be performed taking into account the nephrological perspective.

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Telomerase, shelterin proteins and various interacting factors, named non-shelterin proteins, are involved in the regulation of telomere length (TL). Altered expression of any of these telomere-associated genes can lead to telomere dysfunction, causing genomic instability and disease development. In this study, we investigated the expression profile of a set of non-shelterin genes involved in essential processes such as replication (RPA1), DNA damage repair pathways (MRE11-RAD50-NBS1) and stabilization of telomerase complex (DKC1), in 35 patients with monoclonal gammopathy of undetermined significance (MGUS) and 40 cases with multiple myeloma (MM). Results were correlated with hTERT expression, TL and clinical parameters. Overall, a significant increase in DKC1, RAD50, MRE11, NBS1 and RPA1 expression along with an upregulation of hTERT in MM compared with MGUS was observed (p≤0.032). Interestingly, in both entities high mRNA levels of non-shelterin genes were associated with short TLs and increased hTERT expression. Significant differences were observed for DKC1 in MM (p ≤0.026), suggesting an important role for this gene in the maintenance of short telomeres by telomerase in myeloma plasma cells. With regard to clinical associations, we observed a significant increase in DKC1, RAD50, MRE11 and RPA1 expression in MM cases with high bone marrow infiltration (p≤0.03) and a tendency towards cases with advanced ISS stage, providing the first evidence of non-shelterin genes associated to risk factors in MM. Taken together, our findings bring new insights into the intricate mechanisms by which telomere-associated proteins collaborate in the maintenance of plasma cells immortalization and suggest a role for the upregulation of these genes in the progression of the disease.

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Although many studies have been carried out on monoclonal gammopathy of unknown significances (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM), their classification and underlying pathogenesis are far from elucidated. To discover the relationships among MGUS, SMM, and MM at the transcriptome level, differentially expressed genes in MGUS, SMM, and MM were identified by the rank product method, and then co-expression networks were constructed by integrating the data. Finally, a pathway-network was constructed based on Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, and the relationships between the pathways were identified. The results indicated that there were 55, 78, and 138 pathways involved in the myeloma tumor developmental stages of MGUS, SMM, and MM, respectively. The biological processes identified therein were found to have a close relationship with the immune system. Processes and pathways related to the abnormal activity of DNA and RNA were also present in SMM and MM. Six common pathways were found in the whole process of myeloma tumor development. Nine pathways were shown to participate in the progression of MGUS to SMM, and prostate cancer was the sole pathway that was involved only in MGUS and MM. Pathway-network analysis might provide a new indicator for the developmental stage diagnosis of myeloma tumors.

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The core complex of telomere-associated proteins, named the shelterin complex, plays a critical role in telomere protection and telomere length (TL) homeostasis. In this study, we have explored changes in the expression of telomere-associated genes POT1, TIN2, RAP1 and TPP1, in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). A total of 154 patients: 70 with MGUS and 84 with MM were studied. Real-time quantitative PCR was used to quantify gene expression. TL was evaluated by Terminal Restriction Fragments. Our data showed increased expression of POT1, TPP1, TIN2 and RAP1 in MM with respect to MGUS patients, with significant differences for POT1 gene (p=0.002). In MM, the correlation of gene expression profiles with clinical characteristics highlighted POT1 for its significant association with advanced clinical stages, high calcium and ß2-microglobulin levels (p=0.02) and bone lesions (p=0.009). In multivariate analysis, POT1 expression (p=0.04) was a significant independent prognostic factor for overall survival as well as the staging system (ISS) (p<0.02). Our findings suggest for the first time the participation of POT1 in the transformation process from MGUS to MM, and provide evidence of this gene as a useful prognostic factor in MM as well as a possible molecular target to design new therapeutic strategies.

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The diagnosis of T-cell large granular lymphocytic leukemia in association with other B-cell disorders is uncommon but not unknown. However, the concomitant presence of three hematological diseases is extraordinarily rare. We report an 88-year-old male patient with three simultaneous clonal disorders, that is, CD4+/CD8(weak) T-cell large granular lymphocytic leukemia, monoclonal gammopathy of unknown significance and monoclonal B-cell lymphocytosis. The patient has only minimal complaints and has no anemia, neutropenia or thrombocytopenia. Lymphadenopathy and hepatosplenomegaly were not present. The three disorders were characterized by flow cytometry analysis, and the clonality of the T-cell large granular lymphocytic leukemia was confirmed by polymerase chain reaction. Interestingly, the patient has different B-cell clones, given that plasma cells of monoclonal gammopathy of unknown significance exhibited a kappa light-chain restriction population and, on the other hand, B-lymphocytes of monoclonal B-cell lymphocytosis exhibited a lambda light-chain restriction population. This finding does not support the antigen-driven hypothesis for the development of multi-compartment diseases, but suggests that T-cell large granular lymphocytic expansion might represent a direct antitumor immunological response to both B-cell and plasma-cell aberrant populations, as part of the immune surveillance against malignant neoplasms.

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Diffuse plane normolipemic xanthomatosis (DPNX) is a rare, non-inherited disease that is often associated with systemic diseases, mainly malignant hematological (especially multiple myeloma) or lymph proliferative disorders. The DPNX can precede the appearance of such conditions by several years, so careful follow-up and periodic laboratory examinations are recommended even for patients that seemed to have no underlying disease. We describe a case associated with monoclonal gammopathy. This case shows that dermatological lesions can be the first manifestation of important hematological diseases and so physicians should be familiarized with this entity.

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Diffuse plane normolipemic xanthomatosis (DPNX) is a rare, non-inherited disease that is often associated with systemic diseases, mainly malignant hematological (especially multiple myeloma) or lymph proliferative disorders. The DPNX can precede the appearance of such conditions by several years, so careful follow-up and periodic laboratory examinations are recommended even for patients that seemed to have no underlying disease. We describe a case associated with monoclonal gammopathy. This case shows that dermatological lesions can be the first manifestation of important hematological diseases and so physicians should be familiarized with this entity.

A xantomatose plana difusa normolipêmica (XPDN) é uma dermatose adquirida rara, muitas vezes associada a doenças sistêmicas, nomeadamente neoplasias hematológicas(sobretudo o mieloma múltiplo) ou a processos linfoproliferativos. A XPDN pode preceder o aparecimento dessas doenças em vários anos, sendo por isso recomendada uma vigilância clínica e laboratorial periódica, mesmo para os doentes que aparentemente não apresentam uma doença associada. Descrevemos um caso associado à gamopatia monoclonal. Este caso demonstra a importância das manifestações cutâneas como primeira manifestação de doenças hematológicas importantes e por isso os clínicos devem estar familiarizados com esta entidade.

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Monoclonal gammopathy of undetermined significance (MGUS) is frequently diagnosed in the elderly population. Most physicians will have to evaluate and manage patients with this condition. Recent studies have clarified risk factors, natural history, prognosis and complications of this common condition. This short review discusses basic concepts and recent developments that will facilitate the diagnosis and management of this condition by primary care physicians and specialists in other areas of medicine.

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Revisamos los casos de Mieloma múltiple con amiloidosis primaria en el período comprendido entre 1973 y 1990, encontrando cuatro casos con esta asociación. En todos los pacientes encontramos que el primer motivo de consulta fue la presencia de lesiones en piel caracterizadas por púrpura, nódulos eritemato-violáceos y pápulas normacrómicas o xantocrómicas en piel y mucosas. El propósito de este trabajo es llamar la atención de los dermatólogos acerca de las manifestaciones cutáneas y su importancia como marcador temprano de MM

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