Macroglobulinemia, Waldenstrom, Susceptibility To, 1

Description

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.

Clinical Features

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.

Other Features

Fraumeni et al. (1975) described a kindred in which, in 1 sibship of 9 adults, 4 died of lymphocytic or histiocytic lymphomas and 1, a male, of Waldenstrom macroglobulinemia complicated by adenocarcinoma of the lung. In the next generation, 1 person died of Hodgkin disease; 4 of 9 healthy persons had impaired lymphocyte transformation with phytohemagglutinin, and 3 of these had polyclonal elevation of IgM. Subsequent to the studies, adenocarcinoma of the lung developed in one of those with an immune defect, a woman, and her 3-year-old grandson developed lymphocytic leukemia. This was the first suggestion of a genetic or immunologic basis of lung adenocarcinoma.

Sen et al. (2004) reported the clinical, electrophysiologic, and immunopathologic findings in a patient with progressive retinal degeneration associated with Waldenstrom macroglobulinemia. As the patient had a long history of elevated serum IgM levels and immunopathologic studies confirmed the presence of a serum antibody directed against a retinal antigen in the photoreceptor layer, the paraneoplastic retinopathy was presumed to result from antibodies of the IgM subtype reacting to proteins in the retinal photoreceptors.

Inheritance

Vannotti (1963) observed Waldenstrom macroglobulinemia in mother and son. Seligmann et al. (1963) had an instance of mother and 2 sons affected.

In an Icelandic kindred, Bjornsson et al. (1978) observed a woman with macroglobulinemia who had 2 brothers with monoclonal macroglobulinemia. One brother was asymptomatic, and the other had polyneuropathy and deposits of IgM in peripheral nerves. A third brother died of lymphoreticular disease, which presented as polyneuropathy. Protein abnormalities were found in 3 other sibs and 7 descendants.

Fine et al. (1986) reported the occurrence of Waldenstrom macroglobulinemia in monozygotic twins. The monoclonal IgM in these 2 cases differed in their light chain type and their idiotypic determinants.

Renier et al. (1989) reported 4 brothers with WM. Two of them had kappa type light chain IgM monoclonal components, and 2 had lambda type light chain IgM monoclonal components. Anti-idiotypic rabbit antisera, prepared for each monoclonal component, showed no crossreactivity. The 4 brothers did not share a common HLA haplotype, and a genetic linkage to the major histocompatibility complex could not be demonstrated. Five of 12 relatives had high serum immunoglobulin concentration without monoclonal components.

Cytogenetics

Brown et al. (1967) found an abnormal chromosome in some lymphocytes of 5 members of 1 family; 3 of the 5 had protein abnormalities. See also Elves and Brown (1968).

Schop et al. (2002) found that WM clonal neoplastic cells lack immunoglobulin heavy chain locus (147100) translocations, but have frequent deletions of chromosome 6q.

Schop et al. (2002) found that approximately half of WM patients have 6q deletions. To further clarify the area of minimal deletion of 6q and to address the issue of whether 6q- occurs in IgM MGUS, Schop et al. (2006) studied 12 IgM MGUS in 38 WM patients by fluorescence in situ hybridization (FISH) using probes targeting different chromosomal segments of 6q. No 6q deletions were found in IgM MGUS samples. Of 38 successfully studied WM patients, 21 (55%) showed a deletion of 6q. The area of minimal deletion was between 6q23 and 6q24.3, but the deletion usually encompassed a large fragment of the 6q arm. The results indicated that 6q- can distinguish WM from IgM MGUS and is likely to be a secondary event.

Braggio et al. (2009) performed array-based comparative genomic hybridization (CGH) in 42 WM patients. Overall, 35 (83%) of 42 showed chromosomal abnormalities with a median of 3 abnormalities per patient. A deletion of chromosome 6q was the most common abnormality (40.4% of patients), followed by a gain of chromosome 6p (17%), which was always concomitant with a 6q loss. A minimal deleted region on chromosome 13q14, including MIR15A (609703) and MIR16-1 (609704), was present in 10% of patients. In patients with a 6q deletion, 4 minimal deleted regions were identified, including a region that encompassed the TNFAIP3 gene (191163), a putative tumor suppressor gene.

Mapping

Blattner et al. (1980) found WM in a father and 3 children. Clinical and subclinical autoimmune disorders were also frequent in the family. All persons with WM and all but 1 with autoimmune manifestations had HLA haplotype A2/B8/DRw3. A lod score of 4.86 favored linkage to HLA on chromosome 6p21 and a gene predisposing to lymphoproliferative and autoimmune disorders.

Molecular Genetics

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 (616036), 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.

MYD88 Mutations and Response to Ibrutinib

Treon et al. (2015) sequenced 14 patients with WM who did not have the MYD88 L265P mutation (602170.0004). They identified 3 other MYD88 mutations in the tumors of those patients. All those mutations had also been identified by Ngo et al. (2011) in patients who had diffuse large B-cell lymphoma (DLBCL), particularly the ABC subtype. Treon et al. (2015) noted that although MYD88 mutations other than L265P are uncommon in patients with WM, they make up a quarter of all MYD88 mutations in patients with DLBCL. All the MYD88 mutations that had been found in patients with WM showed high levels of NFKB (see 164011) transactivation in transduction studies (Ngo et al., 2011). Unlike patients with WM, patients with DLBCL showed no association between MYD88 mutation status and the response to ibrutinib. Treon et al. (2015) concluded that their findings supported the association between MYD88 mutations and a response to ibrutinib therapy in patients with WM.

Pathogenesis

Roccaro et al. (2009) and Braggio et al. (2009) presented evidence that WM is associated with activation of the NF-kappa-B pathway. Braggio et al. (2009) identified biallelic inactivation of TNF receptor-associated factor-3 (TRAF3; 601896) in 3 (5.3%) of 57 WM samples. TRAF3 inactivation was associated with transcriptional activation of NF-kappa-B. In addition, 1 of 24 patients with a 6q deletion had an inactivating somatic mutation in TNFAIP3, another negative regulator of NF-kappa-B. Monoallelic deletions of chromosome 6q23, including the TNFAIP3 gene, were identified in 38% of patients, suggesting that haploinsufficiency can predispose to the development of WM. The results indicated that mutational activation of the NF-kappa-B pathway plays a role in the pathogenesis of WM.