Abstract:The pathological progression from benign monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma (SMM) and finally to active myeloma (MM) is poorly understood. Abnormal immunoglobulin G (IgG) glycosylation in myeloma has been reported. Using a glycomic platform composed of hydrophilic interaction UPLC, exoglycosidase digestions, weak anion-exchange chromatography, and mass spectrometry, polyclonal IgG N-glycosylation profiles from 35 patients [MGUS (n = 8), SMM (n = 5), MM (n = 8), comp… Show more
“…While Fleming et al ( 36 ) showed higher sialylation of IgGs from MM patients compared to MGUS patients, Nishiura et al ( 37 ) reported less galactosylated IgGs and, consequently, hyposialylated IgGs, in MM patients compared to MGUS patients and healthy volunteers (HVs). Similarly Mittermayr et al ( 38 ) recently described a decrease of IgG sialylation in a few MM patients in comparison to MGUS patients. In the three studies, the authors studied the glycosylation of all IgG together, without separating mc IgG from polyclonal (pc) IgGs.…”
Multiple myeloma (MM) and its pre-cancerous stage monoclonal gammopathy of undetermined significance (MGUS) allow to study immune responses and the chronology of inflammation in the context of blood malignancies. Both diseases are characterized by the production of a monoclonal immunoglobulin (mc Ig) which for subsets of MGUS and MM patients targets pathogens known to cause latent infection, a major cause of inflammation. Inflammation may influence the structure of both polyclonal (pc) Ig and mc Ig produced by malignant plasma cells via the sialylation of Ig Fc fragment. Here, we characterized the sialylation of purified mc and pc IgGs from 148 MGUS and MM patients, in comparison to pc IgGs from 46 healthy volunteers. The inflammatory state of patients was assessed by the quantification in serum of 40 inflammation-linked cytokines, using Luminex technology. While pc IgGs from MGUS and MM patients showed heterogeneity in sialylation level, mc IgGs from both MGUS and MM patients exhibited a very low level of sialylation. Furthermore, mc IgGs from MM patients were less sialylated than mc IgGs from MGUS patients (p < 0.01), and mc IgGs found to target an infectious pathogen showed a lower level of sialylation than mc IgGs of undetermined specificity (p = 0.048). Regarding inflammation, 14 cytokines were similarly elevated with a p value < 0.0001 in MGUS and in MM compared to healthy controls. MM differed from MGUS by higher levels of HGF, IL-11, RANTES and SDF-1-α (p < 0.05). MGUS and MM patients presenting with hyposialylated pc IgGs had significantly higher levels of HGF, IL-6, tumor necrosis factor-α, TGF-β1, IL-17, and IL-33 compared to patients with hyper-sialylated pc IgGs (p < 0.05). In MGUS and in MM, the degree of sialylation of mc and pc IgGs and the levels of four cytokines important for the anti-microbial response were correlated, either positively (IFN-α2, IL-13) or negatively (IL-17, IL-33). Thus in MGUS as in MM, hyposialylation of mc IgGs is concomitant with increased levels of cytokines that play a major role in inflammation and anti-microbial response, which implies that infection, inflammation, and abnormal immune response contribute to the pathogenesis of MGUS and MM.
“…While Fleming et al ( 36 ) showed higher sialylation of IgGs from MM patients compared to MGUS patients, Nishiura et al ( 37 ) reported less galactosylated IgGs and, consequently, hyposialylated IgGs, in MM patients compared to MGUS patients and healthy volunteers (HVs). Similarly Mittermayr et al ( 38 ) recently described a decrease of IgG sialylation in a few MM patients in comparison to MGUS patients. In the three studies, the authors studied the glycosylation of all IgG together, without separating mc IgG from polyclonal (pc) IgGs.…”
Multiple myeloma (MM) and its pre-cancerous stage monoclonal gammopathy of undetermined significance (MGUS) allow to study immune responses and the chronology of inflammation in the context of blood malignancies. Both diseases are characterized by the production of a monoclonal immunoglobulin (mc Ig) which for subsets of MGUS and MM patients targets pathogens known to cause latent infection, a major cause of inflammation. Inflammation may influence the structure of both polyclonal (pc) Ig and mc Ig produced by malignant plasma cells via the sialylation of Ig Fc fragment. Here, we characterized the sialylation of purified mc and pc IgGs from 148 MGUS and MM patients, in comparison to pc IgGs from 46 healthy volunteers. The inflammatory state of patients was assessed by the quantification in serum of 40 inflammation-linked cytokines, using Luminex technology. While pc IgGs from MGUS and MM patients showed heterogeneity in sialylation level, mc IgGs from both MGUS and MM patients exhibited a very low level of sialylation. Furthermore, mc IgGs from MM patients were less sialylated than mc IgGs from MGUS patients (p < 0.01), and mc IgGs found to target an infectious pathogen showed a lower level of sialylation than mc IgGs of undetermined specificity (p = 0.048). Regarding inflammation, 14 cytokines were similarly elevated with a p value < 0.0001 in MGUS and in MM compared to healthy controls. MM differed from MGUS by higher levels of HGF, IL-11, RANTES and SDF-1-α (p < 0.05). MGUS and MM patients presenting with hyposialylated pc IgGs had significantly higher levels of HGF, IL-6, tumor necrosis factor-α, TGF-β1, IL-17, and IL-33 compared to patients with hyper-sialylated pc IgGs (p < 0.05). In MGUS and in MM, the degree of sialylation of mc and pc IgGs and the levels of four cytokines important for the anti-microbial response were correlated, either positively (IFN-α2, IL-13) or negatively (IL-17, IL-33). Thus in MGUS as in MM, hyposialylation of mc IgGs is concomitant with increased levels of cytokines that play a major role in inflammation and anti-microbial response, which implies that infection, inflammation, and abnormal immune response contribute to the pathogenesis of MGUS and MM.
“…2b , Supplementary Table 5 ). ST6GAL1 , which primarily generates α2,6 linked sialic acids on N- glycans, is overexpressed in multiple cancers [ 18 ] and the increased expression may contribute to aberrant immunoglobulin-G glycosylation seen in MM development [ 19 , 20 ]. Fig.…”
Multiple myeloma (MM) is a biologically heterogeneous malignancy, however, the mechanisms underlying this complexity are incompletely understood. We report an analysis of the whole-genome sequencing of 765 MM patients from CoMMpass. By employing promoter capture Hi-C in naïve B-cells, we identify cis-regulatory elements (CREs) that represent a highly enriched subset of the non-coding genome in which to search for driver mutations. We identify regulatory regions whose mutation significantly alters the expression of genes as candidate non-coding drivers, including copy number variation (CNV) at CREs of MYC and single-nucleotide variants (SNVs) in a PAX5 enhancer. To better inform the interplay between non-coding driver mutations with other driver mechanisms, and their respective roles in oncogenic pathways, we extended our analysis identifying coding drivers in 40 genes, including 11 novel candidates. We demonstrate the same pathways can be targeted by coding and non-coding mutations; exemplified by IRF4 and PRDM1, along with BCL6 and PAX5, genes that are central to plasma cell differentiation. This study reveals new insights into the complex genetic alterations driving MM development and an enhanced understanding of oncogenic pathways.
“…Decreased core fucosylation, appearance of bisecting forms and increased sialylation of serum glycoproteins were observed in patients with light‐chain multiple myeloma (LCMM) . Also in MM, recently low galactosylation and fucosylation was found . Multiple myeloma patients are classified based on the International Myeloma Working Group (IMWG) criteria (Supporting Information Table S1).…”
Multiple myeloma (MM) is an immedicable malignancy of the human plasma cells producing abnormal antibodies (also referred to as paraproteins) leading to kidney problems and hyperviscosity syndrome. In this paper, we report on the N-glycosylation analysis of paraproteins from total human serum as well as the fragment crystallizable region (F ) and fragment antigen binding (F ) κ/λ light chain fractions of papain digested immunoglobulins from multiple myeloma patients. CE-LIF detection was used for the analysis of the N-glycans after endoglycosidase (PNGase F) mediated sugar release and fluorophore labeling (APTS). While characteristic N-glycosylation pattern differences were found between normal control and untreated, treated and remission stage multiple myeloma patient samples at the global serum level, less distinctive changes were observed at the immunoglobulin level. Principal component analysis adequately differentiated the four groups (control and three patient groups) on the basis of total serum N-glycosylation analysis. 12 N-glycan features showed statistically significant differences (p <0.05) among various stages of the disease in comparison to the control at the serum level, while only six features were identified with similar significance at the immunoglobulin level, including the analysis of the partitioned F fragment as well as the F κ and F λ chains.
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