Unraveling the heterogeneity of IgM monoclonal gammopathies: a gene mutational and gene expression study

Abstract

Immunoglobulin M (IgM) monoclonal gammopathies show considerable variability, involving three different stages of presentation: IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), asymptomatic Waldenström's macroglobulinemia (AWM), and symptomatic WM (SWM). Despite recent findings about the genomic and transcriptomic characteristics of such disorders, we know little about the causes of this clinical heterogeneity or the mechanisms involved in the progression from indolent to symptomatic forms. To clarify these matters, we have performed a gene expression and mutational study in a well-characterized cohort of 69 patients, distinguishing between the three disease presentations in an attempt to establish the relationship with the clinical and biological features of the patients. Results showed that the frequency of genetic alterations progressively increased from IgM-MGUS to AWM and SWM. This means that, in contrast to MYD88 p.L265P and CXCR4 WHIM mutations, present from the beginning of the pathogenesis, most of them would be acquired during the course of the disease. Moreover, the expression study revealed a higher level of expression of genes belonging to the Toll-like receptor (TLR) signaling pathway in symptomatic versus indolent forms, which was also reflected in the disease presentation and prognosis. In conclusion, our findings showed that IgM monoclonal gammopathies present higher mutational burden as the disease progresses, in parallel to the upregulation of relevant pathogenic pathways. This study provides a translational view of the genomic basis of WM pathogenesis.

Gene Expression Profile Signature of Aggressive Waldenström Macroglobulinemia with Chromosome 6q Deletion

“…Several studies regarding genes expression analyses in WM were performed, and these studies contributed to elucidate the biology and activated pathway in WM [ 24 – 26 ]. Chng et al firstly conducted genes expression analyses in WM [ 24 ].…”

“…In addition, they hypothesized that lack of PAX5 repression contributed to the upregulation of 3 genes of BCR signaling pathway including CD79, BLNK, and SYK in WM [ 25 ]. Jiménez et al reported that CD79A (B cell activation), IRF3 , MYD88 , MEK1 , P38 (TLR pathway), and WNK1 (MAPK pathway) were overexpressed in WM compared to IgM-MGUS, in which pathways might be responsible for WM cell growth and survival [ 26 ].…”

Identification of a Candidate Gene Set Signature for the Risk of Progression in IgM MGUS to Smoldering/Symptomatic Waldenström Macroglobulinemia (WM) by a Comparative Transcriptome Analysis of B Cells and Plasma Cells

“…Several studies have demonstrated the deregulation of genes associated with the Wnt pathway in B-cell disorders and MM. Indeed, the transcriptional factor LEF1 was under expressed in WM and IgM MGUS vs. CTRLs as well as vs. CLL B-cells [5,15,41,42]. Moreover, LEF1 was over expressed in immature normal B-cells compared to mature normal B-cells [42].…”

“…A gene expression and mutational study demonstrated that genes involved in the Toll-like receptors (TLR) signaling pathways were up-regulated in symptomatic WM vs. indolent forms [5]. Moreover, the authors demonstrated a higher incidence of gene mutations during the process of transition from IgM MGUS to smWM, and sWM.…”

“…IgM MGUS has an overall risk of progression of 1.5-2% per year, and approximately 18% at 10 years to smWM or other lymphoproliferative disorders. While patients with smWM show a probability of progression to WM, amyloidosis or lymphoma of 12% per year, and 65% at 10 years [5,6]. Recurring somatic mutations in MYD88, CXCR4, ARID1A, and CD79B have been found in bone marrow lymphoplasmacytic cells by nextgeneration sequencing (NGS) in patients with WM [7][8][9][10].…”