Waldenström's macroglobulinemia is an indolent, lymphoproliferative disease, characterized by a heterogeneous lymphoplasmacytic bone marrow infiltrate and high immunoglobulin M production. While technological advances over the past several decades have dramatically improved the possibilities of studying the molecular basis of Waldenström's macroglobulinemia, the pathogenesis of the disease remains fragmented. Undoubtedly, research has been successful in uncovering underlying aberrations and deregulated mechanisms in this disease, providing useful information for identifying biomarkers for disease diagnosis, risk stratification and therapeutic intervention, but there is still a long way to go before the pathogenesis of Waldenström's macroglobulinemia is fully revealed. In addition, the low number of in vitro or in vivo models significantly challenges extensive analysis. In this manuscript, we review the molecular basis of this disease.Key words: WM, NF-kB signaling pathway, Jak/STAT, PI3K/Akt, aCGH, IL-6. Waldenström's macroglobulinemia. Haematologica 2012;97(9):1281-1290. doi:10.3324/haematol.2012 This is an open-access paper.
Citation: Braggio E, Philipsborn C, Novak A, Hodge L, Ansell S, and Fonseca R. Molecular pathogenesis of
ABSTRACT
© F e r r a t a S t o r t i F o u n d a t i o n © F e r r a t a S t o r t i F o u n d a t i o nagreed that initiation of therapy was appropriate for patients with constitutional symptoms, such as fever, night sweats or weight loss. The median survival ranges from five to more than ten years, depending on the series analyzed.
10-13The existence of somatic hypermutation in WM indicates a role for antigenic stimulation in the development of WM. [14][15][16] The IgH variable region genes are commonly mutated and the VH3 gene is often used, suggesting antigen exposure and selection. 14,17 Clonality studies have shown clonal IgH and IgL gene rearrangements. The IgH variable region is commonly mutated in WM, but intraclonal variation is usually absent and IgH switching usually does not occur. 18,19 Environmental and inherited factors may contribute to familial IgM-MGUS/WM clusters. Patients with monoclonal gammopathy of undetermined significance (MGUS) are at increased risk for progression to WM. 20 In a population-based study of 1,384 individuals with MGUS, researchers showed an increased risk factor of 46 for developing WM. 20 The rate of progression from IgM-MGUS to WM was further noted to be 1.5-2% a year. [21][22][23] While the development of WM is thought to be sporadic, there are a few studies demonstrating familial linkage and predisposition to the disease. 2,[24][25][26] Both familial clustering of WM and a notable increase (~10 fold) of IgM-MGUS frequency in first-degree relatives of WM patients is suggestive of familial risk. 27 Using the assumption that WM and IgM-MGUS share common susceptibility genes, strong linkages involving chromosomes 1q, 3q, and 4q have been identified. 21 A causal relationship between MGUS/WM and chronic antigenic stimulation has been suggested b...
