Waldenstrom macroglobulinemia (WM) is a malignant B-cell neoplasm characterized by lymphoplasmacytic infiltration of the bone marrow and hypersecretion of monoclonal immunoglobulin M (IgM) protein (review by Vijay and Gertz, 2007). The importance of genetic factors is suggested by ... Waldenstrom macroglobulinemia (WM) is a malignant B-cell neoplasm characterized by lymphoplasmacytic infiltration of the bone marrow and hypersecretion of monoclonal immunoglobulin M (IgM) protein (review by Vijay and Gertz, 2007). The importance of genetic factors is suggested by the observation of familial clustering of WM (McMaster, 2003). Whereas WM is rare, an asymptomatic elevation of monoclonal IgM protein, termed 'IgM monoclonal gammopathy of undetermined significance' (IgM MGUS) is more common. Patients with IgM MGUS can progress to develop WM, at the rate of 1.5% to 2% per year (Kyle et al., 2003). - Genetic Heterogeneity of Waldenstrom Macroglobulinemia One locus for susceptibility to Waldenstrom macroglobulinemia (WM1) maps to chromosome 6p21.3. Another locus (WM2; 610430) maps to chromosome 4q.
The clinical features of Waldenstrom macroglobulinemia are variable, and many patients have asymptomatic or indolent disease. Symptoms are attributable to the extent of tumor infiltration, resulting in anemia or cytopenia when in the bone marrow, as well as ... The clinical features of Waldenstrom macroglobulinemia are variable, and many patients have asymptomatic or indolent disease. Symptoms are attributable to the extent of tumor infiltration, resulting in anemia or cytopenia when in the bone marrow, as well as organomegaly or pulmonary infiltrates. The most common symptom is fatigue attributable to anemia. Elevated levels of circulating IgM may cause an increase in vascular resistance and viscosity, and may cause abnormalities in bleeding and clotting times. Tissue deposition of IgM can occur in renal glomerular loops, intestine, and skin. In addition, the IgM protein has been proven to induce various autoimmune symptoms, such as peripheral neuropathy. Therapy is postponed for asymptomatic patients, and progressive anemia is the most common indication for initiation of treatment (review by Vijay and Gertz, 2007). Royer et al. (2010) analyzed questionnaire-based data from 103 WM patients and 272 unaffected relatives from 35 families with WM and 46 families with mixed WM/B-cell disorders, as well as 28 patients with sporadic disease. The nature and course of the disease process did not differ between those with and without a significant family history. The mean age at diagnosis was 59 years for familial cases and 62.2 years for sporadic cases. Patients with a family history of the disorder were more likely than unaffected relatives to report a history of autoimmune disease (odds ratio (OR) of 2.27) and infections (OR of 2.13), as well as more likely to report exposure to farming (OR of 2.70), pesticides (OR of 2.83), wood dust (OR of 2.86), and organic solvents (OR of 4.21). The study implicated chronic immune stimulation in the development of WM, and suggested that both genetic and environmental factors can modulate susceptibility to development of the disorder.
By microRNA-expression profiling of bone marrow-derived CD19(+) WM cells, Roccaro et al. (2009) identified a specific microRNA signature characterized by increased expression of 6 microRNAs, including MIR155 (609337), MIR363, MIR206 (611599), MIR494, MIR184 (613146), and MIR542-3p. Further study ... By microRNA-expression profiling of bone marrow-derived CD19(+) WM cells, Roccaro et al. (2009) identified a specific microRNA signature characterized by increased expression of 6 microRNAs, including MIR155 (609337), MIR363, MIR206 (611599), MIR494, MIR184 (613146), and MIR542-3p. Further study of MIR155 showed that it regulated proliferation and growth of WM cells in vitro by acting on MAPK/ERK (see 176872), PI3/AKT (164730), and NF-kappa-B (NFKB1; 164011) pathways. Knockdown of MIR155 in WM cells and in mice transfected with WM cells resulted in decreased cell proliferation, decreased adhesion and migration, and changes in cell-cycle regulatory proteins. Mice injected with MIR155-knockdown WM cells showed prolonged survival. Therapeutic agents commonly used in WM, including rituximab, perifosine, and bortezomib, were shown to reduce the expression of 5 of the elevated miRNAs. These data indicated that microRNAs play a pivotal role in the biology of WM, and provided a basis for the development of new microRNA-based targeted therapies in WM. - Somatic Mutation in Bone Marrow Lymphoplasmacytic Lymphoma Cells Treon et al. (2012) performed whole-genome sequencing of bone marrow lymphoplasmacytic lymphoma (LPL) cells in 30 patients with Waldenstrom macroglobulinemia, with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors. Among the patients with Waldenstrom macroglobulinemia, a somatic mutation, L265P (602170.0004), was identified in samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This mutation predicted an amino acid change that triggers IRAK (300283)-mediated NF-kappa-B signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenstrom macroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal-tissue samples from patients with Waldenstrom macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced I-kappa-B-alpha (164008) and NF-kappa-B p65 (164014) phosphorylation, as well as NF-kappa-B nuclear staining, in Waldenstrom macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A (603024) in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenstrom macroglobulinemia who had wildtype MYD88 had somatic variants in MLL2 (602113). Treon et al. (2012) concluded that MYD88 L265P is a commonly recurring mutation in patients with Waldenstrom macroglobulinemia that can be useful in differentiating Waldenstrom macroglobulinemia and non-IgM LPL from B-cell disorders that have phenotypic overlap.