scholarly journals Frequent somatic mutations in D and/or JH segments of Ig gene in Waldenstrom's macroglobulinemia and chronic lymphocytic leukemia (CLL) with Richter's syndrome but not in common CLL

Blood ◽  
1995 ◽  
Vol 85 (7) ◽  
pp. 1913-1919 ◽  
Author(s):  
H Aoki ◽  
M Takishita ◽  
M Kosaka ◽  
S Saito
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutations ◽  
Lymphocytic Leukemia ◽  
Chain Gene ◽  
Waldenström’S Macroglobulinemia ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia ◽  
Richter’S Syndrome

V(D)J recombination and somatic hypermutations are developmentally regulated during B-cell differentiation; therefore, DNA analysis of the Ig gene delineates the cellular origin of B-cell neoplasms. We analyzed the third complementarity-determining region and adjacent regions of the Ig heavy-chain gene of tumor cells from 7 patients with Waldenstrom's macroglobulinemia (WM) and from 10 patients with B-cell chronic lymphocytic leukemia (CLL), 2 of whom progressed to high-grade non-Hodgkin's lymphoma (NHL), ie, Richter's syndrome (RS). There were no intraclonal variations resulting from VH replacements or ongoing somatic mutations in both WM and CLL. We found replacement mutations in the D and/or JH segments in all patients with WM and in 4 of the 10 patients with CLL, including the 2 RS patients. Replacement mutations were clustered in codon 102 of the JH segment. Preferential utilization of the JH4 gene was found in WM (5 of 7 [71.4%]) and in CLL (7 of 10 [70.0%]), and DXP family genes in CLL (5 of 10 [50.0%]). In conclusion, WM and CLL with RS are generated under the influence of antigenic stimulation and selection. However, the majority of CLL may arise from a distinct subpopulation that has the restricted repertoire of nonmutated Ig genes.

scholarly journals Idiotypic cross-reactivity of immunoglobulins expressed in Waldenstrom's macroglobulinemia, chronic lymphocytic leukemia, and mantle zone lymphocytes of secondary B-cell follicles

Blood ◽  
1991 ◽  
Vol 77 (7) ◽  
pp. 1484-1490 ◽  
Author(s):  
O Axelrod ◽  
GJ Silverman ◽  
V Dev ◽  
R Kyle ◽  
DA Carson ◽  
...  
Keyword(s):  
B Cell ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Waldenström’S Macroglobulinemia ◽  
Mantle Zone ◽  
Human Tonsil ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Monoclonal antibodies (MoAbs) specific for autoantibody-associated cross-reactive idiotypes (CRIs) of Waldenstrom's IgM react frequently with the surface Ig (slg) expressed by leukemia cells of patients with chronic lymphocytic leukemia (CLL). Evaluation of the molecular basis for this cross-reactivity indicates that such CRIs are encoded by conserved antibody variable region genes (V genes) that have undergone little or no somatic hypermutation. We find that such anti-CRI MoAbs stain a subpopulation of cells within the mantle zones surrounding the germinal centers of normal human tonsil. In contrast, MoAbs specific for variable region subgroup determinants react with cells in both the mantle zones and germinal centers of secondary B-cell follicles. To test whether mantle zone B cells not reactive with existing anti-CRI MoAbs may express slg bearing as-yet-unrecognized CRIs present on Igs produced by neoplastic cells of some patients with Waldenstrom's macroglobulinemia or CLL, we immunized mice with purified Waldenstrom's IgM that have been characterized for their variable region subgroups using subgroup-specific antisera raised against synthetic peptides. The supernatants of hybridomas generated from the splenocytes of immunized mice were screened for their ability to stain a subpopulation of mantle zone lymphocytes in human tonsil. With this approach, two new anti-CRI MoAbs were identified, designated OAK1 and VOH3. OAK1 binds to a CRI present on a subset of kappa light chains of the VK1 subgroup. VOH3 recognizes a CRI determinant(s) present on a subset of antibody heavy chains of the VH3 subgroup. Flow cytometric analyses demonstrated that OAK1 specifically binds leukemia cells from 5 to 20 patients (25%) with kappa light chain expressing CLL. In addition, VOH3 reacted with the leukemia cells from 1 of 17 (6%) patients tested. The success of these methods demonstrates that the variable regions of the Igs produced by mantle zone B cells share idiotypic determinants with Igs expressed in B-cell CLL (B-CLL) and Waldenstrom's macroglobulinemia.

Clinical Responses to Sildenafil in Waldenstrom’s Macroglobulinemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4926-4926 ◽  
Author(s):  
Steven P. Treon ◽  
Olivier Tournilhac ◽  
Andrew Branagan ◽  
Zachary Hunter ◽  
Lian Xu ◽  
...  
Keyword(s):  
B Cell ◽  
Phosphodiesterase Inhibitor ◽  
Phosphodiesterase Inhibitors ◽  
Fold Increase ◽  
Lymphocytic Leukemia ◽  
Waldenström’S Macroglobulinemia ◽  
Institutional Review ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Waldenstrom’s macroglobulinemia (WM) is an incurable B-cell malignancy. Interestingly, we have observed unusual response activity in five WM patients which appears related to their use of sildenafil, a phosphodiesterase inhibitor used to treat erectile dysfunction. One patient demonstrated a complete remission, while four other patients demonstrated less dramatic, but also unexpected responses associated with sildenafil used at doses of 25–50 mg once to twice a week. In view of these observations, we next evaluated sildenafil for its ability to induce apoptosis of lymphoplasmacytic cells obtained from WM patients. All patients provided written consent for this study which was approved by our institutional review board. Sorted (CD19+, light chain restricted) bone marrow lymphoplasmacytic cells obtained from 6 WM patients were cultured in media alone or with sildenafil (kindly provided by Pfizer Pharmaceuticals, Inc.) at 0.01 ug/ml for 24 hours. These studies demonstrated a mean 2.1 (range 1.24–4.8) fold increase in sildenafil specific/spontaneous apoptosis in lymphoplasmacytic cells from 5 of 5 patients, which included those from a patient who demonstrated a clinical response to sildenafil. Importantly, the concentrations at which apoptosis was observed in these studies is within pharmacologically achievable levels for sildenafil. The results of these studies, along with those recently reported by Sarfati et al (Blood 101:265) who demonstrated caspase mediated apoptosis of B-chronic lymphocytic leukemia (CLL) cells by sildenafil, provide the framework for investigation of sildenafil and related phosphodiesterase inhibitors in the treatment of WM and other B-cell malignancies.

scholarly journals Idiotypic cross-reactivity of immunoglobulins expressed in Waldenstrom's macroglobulinemia, chronic lymphocytic leukemia, and mantle zone lymphocytes of secondary B-cell follicles

Blood ◽  
1991 ◽  
Vol 77 (7) ◽  
pp. 1484-1490
Author(s):  
O Axelrod ◽  
GJ Silverman ◽  
V Dev ◽  
R Kyle ◽  
DA Carson ◽  
...  
Keyword(s):  
B Cell ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Waldenström’S Macroglobulinemia ◽  
Mantle Zone ◽  
Human Tonsil ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Monoclonal antibodies (MoAbs) specific for autoantibody-associated cross-reactive idiotypes (CRIs) of Waldenstrom's IgM react frequently with the surface Ig (slg) expressed by leukemia cells of patients with chronic lymphocytic leukemia (CLL). Evaluation of the molecular basis for this cross-reactivity indicates that such CRIs are encoded by conserved antibody variable region genes (V genes) that have undergone little or no somatic hypermutation. We find that such anti-CRI MoAbs stain a subpopulation of cells within the mantle zones surrounding the germinal centers of normal human tonsil. In contrast, MoAbs specific for variable region subgroup determinants react with cells in both the mantle zones and germinal centers of secondary B-cell follicles. To test whether mantle zone B cells not reactive with existing anti-CRI MoAbs may express slg bearing as-yet-unrecognized CRIs present on Igs produced by neoplastic cells of some patients with Waldenstrom's macroglobulinemia or CLL, we immunized mice with purified Waldenstrom's IgM that have been characterized for their variable region subgroups using subgroup-specific antisera raised against synthetic peptides. The supernatants of hybridomas generated from the splenocytes of immunized mice were screened for their ability to stain a subpopulation of mantle zone lymphocytes in human tonsil. With this approach, two new anti-CRI MoAbs were identified, designated OAK1 and VOH3. OAK1 binds to a CRI present on a subset of kappa light chains of the VK1 subgroup. VOH3 recognizes a CRI determinant(s) present on a subset of antibody heavy chains of the VH3 subgroup. Flow cytometric analyses demonstrated that OAK1 specifically binds leukemia cells from 5 to 20 patients (25%) with kappa light chain expressing CLL. In addition, VOH3 reacted with the leukemia cells from 1 of 17 (6%) patients tested. The success of these methods demonstrates that the variable regions of the Igs produced by mantle zone B cells share idiotypic determinants with Igs expressed in B-cell CLL (B-CLL) and Waldenstrom's macroglobulinemia.

Identification of two DNA methylation subtypes of Waldenström's macroglobulinemia with plasma and memory B cell features

Blood ◽  
2020 ◽  
Author(s):  
Damien Roos-Weil ◽  
Brian Giacopelli ◽  
Marine Armand ◽  
Véronique Della Valle ◽  
Hussein Ghamlouch ◽  
...  
Keyword(s):  
Dna Methylation ◽  
B Cell ◽  
Plasma Cells ◽  
Surface Expression ◽  
B Cell Differentiation ◽  
Waldenström’S Macroglobulinemia ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
B Cell Subsets ◽  
Waldenström's Macroglobulinemia

Epigenetic changes during B cell differentiation generates distinct DNA methylation signatures specific for B cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenström's macroglobulinemia (WM) is a complex B cell malignancy uniquely comprised of a mixture of lymphocytic and plasmacytic phenotypes. Here we integrated genome-wide DNA methylation, transcriptome, mutation and other phenotypic features of tumor cells from 35 MYD88-mutated WM patients in relation to normal plasma and B cell subsets. We discovered that WM patients naturally segregate into two groups according to DNA methylation patterns, related to normal MBC and PC profiles, and reminiscent of other memory and plasma cell-derived malignancies. Concurrent analysis of DNA methylation changes in normal and WM development were used to capture tumor-specific events, highlighting a selective reprogramming of enhancer regions in MBC-like WM and repressed and heterochromatic regions in PC-like WM. MBC-like WM hypomethylation was enriched in motifs belonging to PU.1, TCF3 and OCT2 transcription factors and involved elevated MYD88/TLR pathway activity. PC-like WM displayed marked global hypomethylation and selective overexpression of histone genes. Finally, WM subtypes exhibited differential genetic, phenotypic and clinical features. MBC-like WM harbored significantly more clonal CXCR4 mutations (P=0.015), deletion 13q (P=0.006), splenomegaly (P=0.02) and thrombocytopenia (P=0.004), while PC-like WM harbored more deletion 6q (P=0.012), gain 6p (P=0.033), had increased frequencies of IGHV3 genes (P=0.002), CD38 surface expression (P=4.1e-5), and plasmacytic differentiation features (P=0.008). Together our findings illustrate a novel approach to subclassify WM patients using patterns of DNA methylation and reveal divergent molecular signatures among WM patients.

scholarly journals Poor Correlation between Pneumococcal IgG and IgM Titers and Opsonophagocytic Activity in Vaccinated Patients with Multiple Myeloma and Waldenstrom's Macroglobulinemia

2016 ◽  
Vol 23 (4) ◽  
pp. 379-385 ◽  
Author(s):  
Johanna Karlsson ◽  
Lucy Roalfe ◽  
Harriet Hogevik ◽  
Marta Zancolli ◽  
Björn Andréasson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Elderly Subjects ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Waldenström’S Macroglobulinemia ◽  
Control Subjects ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

ABSTRACTPatients with multiple myeloma and other B cell disorders respond poorly to pneumococcal vaccination. Vaccine responsiveness is commonly determined by measuring pneumococcal serotype-specific antibodies by enzyme-linked immunosorbent assay (ELISA), by a functional opsonophagocytosis assay (OPA), or by both assays. We compared the two methods in vaccinated elderly patients with multiple myeloma, Waldenstrom's macroglobulinemia, and monoclonal gammopathy of undetermined significance (MGUS). Postvaccination sera from 45 patients (n= 15 from each patient group) and 15 control subjects were analyzed by multiplexed OPA for pneumococcal serotypes 4, 6B, 14, and 23F, and the results were compared to IgG and IgM antibody titers measured by ELISA. While there were significant correlations between pneumococcal OPA and IgG titers for all serotypes among the control subjects (correlation coefficients [r] between 0.51 and 0.85), no significant correlations were seen for any of the investigated serotypes in the myeloma group (r= −0.18 to 0.21) or in the group with Waldenstrom's macroglobulinemia (borderline significant correlations for 2 of 4 serotypes). The MGUS group resembled the control group by having good agreement between the two test methods for 3 of 4 serotypes (r= 0.53 to 0.80). Pneumococcal postvaccination IgM titers were very low in the myeloma patients compared to the other groups and did not correlate with the OPA results. To summarize, our data indicate that ELISA measurements may overestimate antipneumococcal immunity in elderly subjects with B cell malignancies and that a functional antibody test should be used specifically for myeloma and Waldenstrom's macroglobulinemia patients.

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