Immunoglobulin variable domain high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

Abstract

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare multisystem disease resulting from an underlying plasma cell (PC) dyscrasia. The pathophysiology of the disease remains unclear, but the role of the monoclonal immunoglobulin (Ig) light chain (LC) is strongly suspected because of the highly restrictive usage of 2 λ variable (V) domains (IGLV1-40 and IGLV1-44) and the general improvement of clinical manifestations after PC clone-targeted treatment. However, the diagnostic value of Ig LC sequencing, especially in the case of incomplete forms of the disease, remains to be determined. Using a sensitive high-throughput Ig repertoire sequencing on RNA (rapid amplification of cDNA ends-based repertoire sequencing [RACE-RepSeq]), we detected a λ LC monoclonal expansion in the bone marrow (BM) of 83% of patients with POEMS syndrome, including some in whom BM tests routinely performed to diagnose plasma cell dyscrasia failed to detect λ+ monoclonal PCs. Twenty-four (83%) of the 29 LC clonal sequences found were derived from the IGLV1-40 and IGLV1-44 germline genes, as well as 2 from the closely related IGLV1-36 gene, and all were associated with an IGLJ3*02 junction (J) gene, confirming the high restriction of VJ region usage in POEMS syndrome. RACE-RepSeq VJ full-length sequencing additionally revealed original mutational patterns, the strong specificity of which might crucially help establish or eliminate the diagnosis of POEMS syndrome in uncertain cases. Thus, RACE-RepSeq appears as a sensitive, rapid, and specific tool to detect low-abundance PC clones in BM and assign them to POEMS syndrome, with all the consequences for therapeutic options.

Identification of An Immune-related Signature in Predicting Prognosis of Oral Squamous Cell Carcinoma Patients

“…Other immune-related genes are relatively novel and scattered evidence has reported for their roles in human diseases. For example, IGLV1-36 gene is a potentially therapeutic option for POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome [39]. Also, LINC01508, a long non-coding RNAs, the downregulation of LINC01508 contributes to cisplatin resistance in ovarian cancer [40].…”

Multicentric Castleman disease and the evolution of the concept

“…Patients usually present with sclerotic bone lesions, rather than the typical osteolytic lesions seen in multiple myeloma. Most patients have a λ light chain-expressing plasma cell clone in their bone marrow, with highly restrictive usage of two λ variable (V) domains (IGLV1-40 and IGLV1-44) 92 . Half of patients show lymphoid aggregates in the bone marrow biopsy, with distinctive rimming by plasma cells.…”

Strategies for Immunomonitoring after Vaccination and during Infection

“…For instance, BCR profiling led to a better understanding of an alternative to an isotypic switch in the B cell (locus suicide recombination), resulting in the deletion of a constant region that could restrain the activation of mature B cells [95]. Technologies depicting the Ig repertoire and evaluating the redundancy of clonal sequences have been found to be valuable in multiorgan diseases [96] but also in vaccination [97]. All these technologies are a real opportunity to characterize small cell populations and gene pathway implications, and to decipher the immune response in infectious disease and vaccines [98].…”