Nucleic Acid Biomarkers in Waldenström Macroglobulinemia and IgM-MGUS: Current Insights and Clinical Relevance

Abstract

Waldenström Macroglobulinemia (WM) is an indolent lymphoplasmacytic lymphoma, characterized by the production of excess immunoglobulin M monoclonal protein. WM belongs to the spectrum of IgM gammopathies, ranging from asymptomatic IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), through IgM-related disorders and asymptomatic WM to symptomatic WM. In recent years, its complex genomic and transcriptomic landscape has been extensively explored, hereby elucidating the biological mechanisms underlying disease onset, progression and therapy response. An increasing number of mutations, cytogenetic abnormalities, and molecular signatures have been described that have diagnostic, phenotype defining or prognostic implications. Moreover, cell-free nucleic acid biomarkers are increasingly being investigated, benefiting the patient in a minimally invasive way. This review aims to provide an extensive overview of molecular biomarkers in WM and IgM-MGUS, considering current shortcomings, as well as potential future applications in a precision medicine approach.

Dysfunctions of innate and adaptive immune tumor microenvironment in Waldenström macroglobulinemia

“…Recently, the MYDD88 L265P mutation that is associated with genomic pathogenesis of WM was also shown to be present in earlier pre-B progenitors in WM. [12][13][14][15][16] In subsequent B cell maturation, immature cells (I1-3) expressed CD19+, CD20+, CD27À, CD10 low , IgM+, IgD À/low , while subsets of transitional cells (T1-2) were characterized by CD19+, CD27À, CD10À, IgM+, but with heterogeneous IgD expression. Naïve (N) mature B cells expressing CD19+, CD20+, CD38 low , CD10À, CD27À and coexpressing IgM+ IgD++ leave the BM and recirculate between the peripheral blood and lymphoid tissues.…”

“…Although the expression profiles are quite stable, modulation in the expression levels of markers shows aberrant marker expression, especially in pre‐BII cells of WM patients, which observed a significant decrease in aberrant expression phenotype of CD10, CD19, CD22 and CD38, whereas an increase in expression of CD45. Recently, the MYDD88 L265P mutation that is associated with genomic pathogenesis of WM was also shown to be present in earlier pre‐B progenitors in WM 12‐16 . In subsequent B cell maturation, immature cells (I1‐3) expressed CD19+, CD20+, CD27−, CD10 low , IgM+, IgD −/low , while subsets of transitional cells (T1‐2) were characterized by CD19+, CD27−, CD10−, IgM+, but with heterogeneous IgD expression.…”

Monoclonal Gammopathies of Clinical Significance: A Critical Appraisal

“…In accordance with recent international consensus recommendations, two subtypes of Ig M MGUS should be differentiated: IgM MGUS of PC type, which is considered a precursor of MM, and IgM MGUS, NOS, including all cases with a MYD88 mutation, those with detectable monotypic/monoclonal B-cells but without abnormal lymphoplasmacytic aggregates diagnostic of lymphoplasmacytic lymphoma, and those lacking evidence of other small B-cell neoplasms. Hence, MYD88 mutation should be incorporated into routine workups [ 2 , 38 , 39 , 40 , 41 ].…”

Liquid Biopsy in Cancer: Focus on Lymphoproliferative Disorders

“…Some mutations detectable in cfDNA could also give information about drug sensitivity/resistance, as in the case of MYD88 variants that were reported to predict response to ibrutinib, in DLBCL patients [ 202 , 203 ]. Importantly a high concordance rate between peripheral blood and BM cancer cells, in terms of both MYD88 and CXCR4 mutational status, has been clearly demonstrated in WM patients, in terms of both disease status and drug resistance [ 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 ].…”