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Acquired ibrutinib resistance due to BTKCys481 mutations occurs in B-cell malignancies, including those with MYD88 mutations. BTKCys481 mutations are usually subclonal, and their relevance to clinical progression remains unclear. Moreover, the signaling pathways that promote ibrutinib resistance remain to be clarified. We therefore engineered BTKCys481Ser and BTKWT expressing MYD88-mutated Waldenström macroglobulinemia (WM) and activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) cells and observed reactivation of BTK-PLCγ2-ERK1/2 signaling in the presence of ibrutinib in only the former. Use of ERK1/2 inhibitors triggered apoptosis in BTKCys481Ser-expressing cells and showed synergistic cytotoxicity with ibrutinib. ERK1/2 reactivation in ibrutinib-treated BTKCys481Ser cells was accompanied by release of many prosurvival and inflammatory cytokines, including interleukin-6 (IL-6) and IL-10 that were also blocked by ERK1/2 inhibition. To clarify if cytokine release by ibrutinib-treated BTKCys481Ser cells could protect BTKWT MYD88-mutated malignant cells, we used a Transwell coculture system and showed that nontransduced BTKWT MYD88-mutated WM or ABC DLBCL cells were rescued from ibrutinib-induced killing when cocultured with BTKCys481Ser but not their BTKWT-expressing counterparts. Use of IL-6 and/or IL-10 blocking antibodies abolished the protective effect conferred on nontransduced BTKWT by coculture with BTKCys481Ser expressing WM or ABC DLBCL cell counterparts. Rebound of IL-6 and IL-10 serum levels also accompanied disease progression in WM patients with acquired BTKCys481 mutations. Our findings show that the BTKCys481Ser mutation drives ibrutinib resistance in MYD88-mutated WM and ABC DLBCL cells through reactivation of ERK1/2 and can confer a protective effect on BTKWT cells through a paracrine mechanism. [ABSTRACT FROM AUTHOR]

The article discusses research which showed that malignant pleural effusions in Waldenström macroglobulinaemia (WM) can be identified with the use of MYD88 mutations. Topics discussed include the characteristics of WM, a B-cell malignancy by bone marrow (BM) infiltration, clinical presentation and diagnostic work-up for the pleural effusions, differential diagnosis with lymphocyte-rich effusions and factors that can hinder the identification of a clonal population.

Ibrutinib produces high response rates and durable remissions in Waldenström macroglobulinemia (WM) that are impacted by MYD88 and CXCR4WHIM mutations. Disease progression can developonibrutinib, although the molecular basis remains to be clarified. We sequenced sorted CD191 lymphoplasmacytic cells from 6WMpatients who progressed after achieving major responses on ibrutinib using Sanger, TA cloning and sequencing, and highly sensitive and allele-specific polymerase chain reaction (AS-PCR) assays that we developed for Bruton tyrosine kinase (BTK) mutations. AS-PCR assays were used to screen patients with and without progressive disease on ibrutinib, and ibrutinib-naıve disease. Targeted next-generation sequencing was used to validate AS-PCR findings, assess for other BTK mutations, and other targets in B-cell receptor and MYD88 signaling. Among the 6 progressing patients, 3 had BTKCys481 variants that included BTKCys481Ser(c.1635G>C and c.1634T>A) and BTKCys481Arg(c.1634T>C). Two of these patients had multiple BTK mutations. Screening of 38 additional patients on ibrutinib without clinical progression identifiedBTKCys481 mutations in 2 (5.1%) individuals, both of whom subsequently progressed. BTKCys481 mutations were not detected in baseline samples or in 100 ibrutinib-naive WM patients. Using mutated MYD88 as a tumor marker, BTKCys481 mutations were subclonal, with a highly variable clonal distribution. Targeted deep-sequencing confirmed AS-PCR findings, and identified an additional BTKCys481Tyr(c.1634G>A) mutation in the 2 patients with multiple otherBTKCys481 mutations, as well asCARD11Leu878Phe(c.2632C>T) andPLCg2Tyr495His(c.1483T>C) mutations. Four of the 5 patients with BTKC481 variants were CXCR4 mutated. BTKCys481 mutations are common in WM patients with clinical progression on ibrutinib, and are associated with mutated CXCR4. [ABSTRACT FROM AUTHOR]

In Waldenström macroglobulinaemia ( WM), the mechanism(s) responsible for repression of B-cell differentiation remains unknown. We found that expression of SPIB and ID 2 were significantly increased and decreased, respectively, in WM lymphoplasmacytic cells ( LPC). Ectopic expression of SPIB in healthy donor CD19+ cells inhibited plasmacytic differentiation in conjunction with decreased transcription of IRF 4 and XBP 1 spliced form. In primary WM LPC, knock-down of SPIB induced plasmacytic differentiation in conjunction with increased transcription of PRDM 1, XBP 1 spliced form, IRF 4 and ID 2. Knock-down of SPIB also led to decreased BCL 2 expression. Given that SPIB is a direct target of POU 2 AF 1 ( OBF 1) in complex with POU 2 F 2 or POU 2 F 1, we next examined their expression in WM LPC. POU 2 F 2 transcription, as well as POU2F2 and POU2 AF1 protein expression was higher in WM LPC. Ectopic expression of POU 2 F 2 in healthy donor CD19+ cells induced transcription of SPIB and suppressed transcription of PRDM 1 and IRF 4. Chromatin immunoprecipitation analysis in BCWM.1 WM cells confirmed binding of POU2F2 and POU2 AF1 in SPIB and ID 2 promoters. These findings establish a molecular hierarchy among POU 2 F 2, SPIB and ID 2 during B-cell differentiation, and suggest that aberrant expression of these transcription factors plays an important role in arresting plasmacytic differentiation in WM. [ABSTRACT FROM AUTHOR]

The article focuses on a study regarding the role of B-cell selection in determination of the MYD88 mutation status in waldenstrom macroglobulinemia (WM). It mentions that WM is characterized by bone marrow (BM) with lymphoplasmacytic lymphoma and helps in the production of a monoclonal immunoglobulin (Ig) M protein. It also mentions the importance of MYD88 mutational status in diagnostic, prognostic and treatment of WM patients.

By whole-genome and/or Sanger sequencing, we recently identified a somatic mutation (MYD88 L265P) that stimulates nuclear factor κB activity and is present in >90% of Waldenström macroglobutinemia (WM) patients. MYD88 L265P was absent in 90% of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) patients. We therefore developed conventional and real-time allele-specific polymerase chain reaction (AS-PCR) assays for more sensitive detection and quantification of MYD88 L265P. Using either assay, MYD88 L265P was detected in 97 of 104 (93%) WM and 13 of 24 (54%) IgM MGUS patients and was either absent or rarely expressed in samples from splenic marginal zone lymphoma (2/20; 10%), CLL (1/26; 4%), multiple myeloma (including IgM cases, 0/14), and immunoglobulin C MGUS (0/9) patientsas well as healthy donors (0/40; P < 1.5 × 10-5 for WM vs other cohorts). Real-time AS-PCR identified IgM MGUS patients progressing to WM and showed a high rate of concordance between MYD88 L265P ΔCT and BM disease involvement (r = 0.89, P = .008) in WM patients undergoing treatment. These studies identify MYD88 L265P as a widely present mutation in WM and IgM MGUS patients using highly sensitive and specific AS-PCR assays with potential use in diagnostic discrimination and/or response assessment. The finding of this mutation in many IgM MGUS patients suggests that MYD88 L265P may be an early oncogenic event in WM pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Little is known about the epidemiology and etiology of Waldenstrom macroglobulinemia (WM). Despite several studies of the relation between family history and B-cell disorders and WM, family history of non-hematologic cancers has not been systematically investigated. We thus examined associations of family history of breast, colorectal, lung, ovarian, and prostate cancers with WM. Methods: All probands aged 20–79 years with bone marrow biopsy-confirmed diagnosis of WM between May 1, 1999 and January 1, 2010 at the Bing Center for Waldenstrom Macroglobulinemia were eligible for inclusion in our analysis. We reviewed medical records for eligible probands to determine family history of cancer (defined as a cancer diagnosis for ≥1 first-degree relative(s) of the proband). Using expected values constructed from the United States National Health Interview Survey, we estimated age- and race-standardized rate ratios (RRs) for family history of breast, colorectal, lung, ovarian, and prostate cancers by WM subtype. Results: Family history of prostate cancer had the largest overall rate ratio (RR=1.4, 95% confidence limits [CL]: 1.1, 1.7), and among sporadic cases, family history of prostate and breast cancer had the largest rate ratios (prostate: RR=1.3, 95% CL: 1.1, 1.7; breast: RR=1.3, 95% CL: 1.2, 1.6). Conclusion: Our study suggests that it may be worthwhile to pursue these associations in a case–control study with uniform selection and data collection for cases and controls, and at least some record-based information on family history. [Copyright &y& Elsevier]

Objectives: Waldenstrom Macroglobulinemia (WM) is a B-cell neoplasm characterised by secretion of IgM by lymphoplasmacytic bone marrow cells and by cytopenias and hypogammaglobulinemia in a subset of patients. Beta-2 microglobulin (b2m) is a major prognostic factor in WM and the heavy chain of HLA class I molecules, which are known to have immunosuppressive properties and have been implicated in the pathogeny of several malignancies. Methods: We assessed the serum levels of the total soluble HLA-I molecules and the HLA-Gs molecules in 105 patients with IgM-related disorders [WM ( n = 42) and IgM MGUS ( n = 63)], and compared the results to 41 healthy subjects. Results: We found higher levels of HLA-Is in WM, compared to IgM MGUS and healthy donors. HLA-Gs levels were similar in WM and in IgM MGUS, but higher than in healthy donors. The association between HLA-Is at the cut-off of 1.8 μg/mL and known markers of poor prognosis was then evaluated among WM patients using univariate and multivariate methods. Based on this, high HLA-Is level was strongly associated with high serum β2M level >3 mg/L [OR = 2, (CI 95% 1.1–5.7); P = 0.04], age > 65 yrs [OR = 1.5, (CI 95% 0.5–4.1), P = 0.06] and haemoglobin ≤11.5 g/dL [OR = 3.3, (CI 95% 1.2–9.7); P = 0.03]. High levels of serum HLA-Is were also found in patients with cryoglobulinemia, however irrespectively of WM or IgM-MGUS status. Conclusion: Together our results suggest a possible role for soluble MHC class I molecules in WM disease. Further investigations are necessary to further demonstrate the prognostic impact of soluble MHC class I molecules in Waldenstrom Macroglobulinemia. [ABSTRACT FROM AUTHOR]