Molecular Analysis of the VH Gene Usage in a Familial Case of Waldenstrom’s Macroglobulinemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1005-1005
Author(s):  
Marina P. Siakantaris ◽  
Marie-Christine Kyrtsonis ◽  
Konstantinos Lilakos ◽  
Maria K. Angelopoulou ◽  
S. Vavourakis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Healthy Individuals ◽  
Waldenström’S Macroglobulinemia ◽  
Three Generations ◽  
Mild Anemia ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Lymphoplasmacytic Infiltration ◽  
Waldenström's Macroglobulinemia

Abstract Waldenstrom’s Macroglobulinemia (WM) is a rare lymphoproliferative disorder characterized by lymphoplasmacytic infiltration of the bone marrow and/or other tissues and the presence of a serum monoclonal IgM. The etiology of the disease is still unknown but the identification of family clusters may contribute to the understanding of its pathogenesis. In this study we present a family with 4 members affected by WM consisting of three generations; 2 sisters of the first generation were both suffering from WM. One of them presented to our section with mild anemia, a monoclonal serum IgM compound, 80% infiltration by lymphoplasmacytes in the bone marrow and the diagnosis of WM was made. Her sister was also suffering from WM but followed in another Centre. Our patient had two sons that at the age of 52 and 46 years presented a serum monoclonal IgM. At presentation, the first one had a monoclonal IgM value of 1680 mg/dl and a 40% BM lymphoplasmacytic infiltration with no other findings, signs or symptoms; he is regularly followed in our section for 30 months and his disease is stable. The second son, presented with a serum monoclonal IgM value of 886 mg/dl and a 10% BM infiltration by monoclonal lymphoplasmacytes and plasmacytes and was initially characterized as having an IgM-MGUS; while under follow-up examination only, he developed peripheral neuropathy with positive anti-Mag antibodies and improved with rituximab administration. Nor the mother or the sons had HCV antibodies. The first son has 3 children and the second two. Buccal and blood DNA was analysed for the IgH rearrangement by PCR. The PCR products after ligation and cloning were sequenced in an automated sequencer. Sequences obtained from each sample were aligned with germline sequences in the BLAST directory. No Ig rearrangements were detected in buccal DNA. Monoclonality was demonstrated in all affected members and in 2 healthy individuals of the third generation by PCR while immunophenotyping did not show evidence of disease in those two members. VH3 family was expressed at the highest frequency (80%). Different gene segments were recognized for the analysed sequences. D segments were attributed in all sequences. All affected and 1 healthy member had mutated VH genes. This is the first study of a family with WM consisting of three generations and reporting blood monoclonality of healthy individuals by molecular methods. The biologic value of the finding remains to be seen. Further study and a long follow-up is needed to clarify this issue.

Primary systemic amyloidosis: a rare complication of immunoglobulin M monoclonal gammopathies and Waldenström's macroglobulinemia.

1993 ◽  
Vol 11 (5) ◽  
pp. 914-920 ◽  
Author(s):  
M A Gertz ◽  
R A Kyle ◽  
P Noel
Keyword(s):  
Bone Marrow ◽  
Median Survival ◽  
Subcutaneous Fat ◽  
Immunoglobulin M ◽  
Entire Group ◽  
Waldenström’S Macroglobulinemia ◽  
Cardiac Amyloid ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

PURPOSE To determine the natural history of amyloidosis associated with Waldenström's macroglobulinemia and immunoglobulin M (IgM) monoclonal gammopathy. PATIENTS AND METHODS From January 1968 to September 1990, 50 patients with a serum IgM monoclonal protein and biopsy-proven amyloidosis were evaluated at the Mayo Clinic. There were 32 men and 18 women (age range, 43 to 93 years). RESULTS Percentages of patients presenting with cardiac, renal, hepatic, and pulmonary amyloid were 44%, 32%, 14%, and 10%, respectively. Forty-two percent of the patients had an M protein value greater than 1.5 g/dL, and 12% had an M component greater than 3 g/dL. Subcutaneous fat, rectum, and bone marrow showed amyloid in 84%, 72%, and 50%, respectively, providing a simple technique for diagnosing amyloidosis. The bone marrow biopsy was consistent with Waldenström's macroglobulinemia in 10, a plasma-cell proliferative disorder in 10, and lymphoma or a lymphoproliferative disorder in 11; results were normal, nondiagnostic, or hypercellular in 17. Forty-three of 50 patients died. The median survival of the entire group was 24.6 months. Fifty-three percent of deaths were due to cardiac amyloid, 12% to respiratory failure, 7% to macroglobulinemia, 7% to liver failure, and 7% to kidney failure. CONCLUSION The presence of amyloid cardiomyopathy and an increased creatinine concentration at diagnosis had an adverse impact on survival. Of the 22 patients who presented with cardiomyopathy, the median survival was 11.1 months, with only two surviving longer than 5 years. The median survival of the 28 patients without cardiomyopathy at diagnosis was 27 months, with eight 5-year survivors (P = .013). All eight amyloid deposits studied stained for Ig light chain, indicating that this amyloidosis is of the primary (AL) type.

B-Lymphocyte Stimulator (BLyS) Is Highly Expressed in Waldenstrom’s Macroglobulinemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2291-2291
Author(s):  
Stephen M. Ansell ◽  
Deanna M. Grote ◽  
Steven C. Ziesmer ◽  
Thomas E. Witzig ◽  
Robert A. Kyle ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Waldenström’S Macroglobulinemia ◽  
B Lymphocyte Stimulator ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia ◽  
Normal Controls

Abstract Waldenstrom’s macroglobulinemia is a serious and frequently fatal illness, however many of the mechanisms leading to this disease are not yet known. It is clear, however, that there is dysregulation of the balance between cell proliferation and programmed cell death. BLyS (B-lymphocyte stimulator) is a newly identified TNF family member expressed by monocytes, macrophages, and dendritic cells. BLyS has been shown to be critical for maintenance of normal B cell development and homeostasis, and has been found to stimulate lymphocyte growth. BLyS is overexpressed in a variety of B-cell malignancies and has been shown to inhibit apoptosis in malignant B-cells. Studies of the effects of BLyS on B cell physiology have shown that it also regulates immunoglobulin secretion. To determine the relevance of the BLyS receptor-ligand system in Waldenstrom’s macroglobulinemia, we examined malignant B cells from 5 patients with Waldenstrom’s macroglobulinemia for their ability to bind soluble BLyS and for the expression of the known BLyS receptors, TACI, BAFF-R, or BCMA. The malignant B cells were found to bind BLyS and express BAFF-R and TACI. BCMA expression was undetectable. We then determined the expression of BLyS in bone marrow specimens from 5 patients with Waldenstrom’s macroglobulinemia by immunohistochemistry and compared it to the expression in 5 normal bone marrow specimens. The lymphoplasmacytic cell infiltrate in the bone marrow of patients with Waldenstrom’s macroglobulinemia showed significantly increased BLyS expression. We further determined the serum BLyS levels by ELISA in stored serum specimens from patients with Waldenstrom’s macroglobulinemia (n=20), and compared them to serum BLyS levels in other patients with lymphoplasmacytic lymphoma without elevated immunoglobulin levels (n=10) and to serum levels in normal controls (n=50). Serum BLyS levels in Waldenstrom’s patients (mean: 49.6ng/ml) as well as those in patients with lymphoplasmacytic lymphoma (mean; 46.7ng/ml) were significantly higher than normal controls (mean 12.6ng/ml). In conclusion, we have demonstrated that malignant B cells from patients with Waldenstrom’s macroglobulinemia express the receptors for BLyS and can bind soluble BLyS. Furthermore, we have found that serum BLyS levels are significantly elevated in patients with Waldenstrom’s macroglobulinemia when compared to controls. Strategies to inhibit BLyS may potentially have significant therapeutic efficacy in Waldenstrom’s macroglobulinemia.

Histone Deacetylase Inhibitors Demonstrate Significant Preclinical Activity as Single Agents, and in Combination with Bortezomib in Waldenstrom's Macroglobulinemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4785-4785
Author(s):  
Jenny Sun ◽  
Lian Xu ◽  
Hsiuyi Tseng ◽  
Bryan Ciccarelli ◽  
Mariateresa Fulciniti ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Histone Deacetylase Inhibitors ◽  
Conflicts Of Interest ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Waldenström’S Macroglobulinemia ◽  
Over Expression ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 4785 Waldenstrom's Macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by bone marrow infiltration of CD19+ cells and production of a monoclonal IgM protein. Despite advances in treatment, WM remains incurable. As part of these efforts we sought to define the role of HDAC-inhibitors in WM. Gene expression profiling of bone marrow CD19+ cells from 30 WM patients and 10 healthy donors showed over-expression of HDAC4, HDAC9, and Sirt5 in WM patients. Evaluation of the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA or Vorinostat), Trichostatin A (TSA), LBH-589 (Panobinostat), and sirtinol demonstrated dose dependent killing of BCWM.1 cells with IC50 of 3.5 uM, 70 nM, 0.8 uM, and 30 uM, respectively, whilst the combination of these agents with bortezomib resulted in at least additive tumor cell killing. TSA is more potent than bortezomib in inducing apoptosis in primary WM tumor cells in patients with prior treatment. TSA and bortezomib showed synergistic effect in 25% of the patients samples tested. We also observed that TSA and bortezomib-induced apoptosis of BCWM.1 cells depended on the activation of a similar set of caspases. Conversely, changes in cell cycle regulators were distinctly different between TSA and bortezomib treated BCWM.1 cells. The results of these studies demonstrate over-expression of distinct members of HDAC in WM cells, and provide a framework for the examination of HDAC-inhibitors as monotherapy, as well as combination therapy with bortezomib in the treatment of WM. Disclosures: No relevant conflicts of interest to declare.

The Role of Angiopoietins System in Waldenstrom's Macroglobulinemia: Correlations with Marrow Microvessel Density and Survival

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3901-3901
Author(s):  
Efstathios Kastritis ◽  
Evangelos Eleutherakis-Papaiakovou ◽  
Maria Gavriatopoulou ◽  
Dimitrios Christoulas ◽  
Athanasios Papatheodorou ◽  
...  
Keyword(s):  
Microvessel Density ◽  
Prognostic Significance ◽  
Serum Levels ◽  
Waldenström’S Macroglobulinemia ◽  
Vessel Formation ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia ◽  
Angiogenic Cytokines

Abstract Abstract 3901 Angiogenesis is elevated in many hematological malignancies, but there is limited information for angiogenesis in Waldenstrom's macroglobulinemia (WM). Several cytokines including VEGF (and its major angiogenic component VEGF-A), bFGF, angiogenin and angiopoietin-1 (Ang-1) and 2 (Ang-2) participate in the neoangiogenesis process. We have previously shown that circulating angiogenic cytokines correlate with disease severity in WM (Anagnostopoulos et al, Br J Haematol 2007;137:560–8), while it has been reported that the bone marrow (BM) microvessel density (MVD) is increased in 30%-40% of patients with WM (Rajkumar et al, Semin Oncol 2003;30:265–9). The ratio of Ang-1/Ang-2 correlates with survival in multiple myeloma, but there is no information for the prognostic value of the angiopoietins and other angiogenic cytokines in WM. To address this issue, we studied the serum levels of VEGF, VEGF-A, bFGF, angiogenin, Ang-1 and Ang-2 in the serum of 55 patients with symptomatic WM before the administration of any kind of therapy, in 5 patients with asymptomatic WM (AWM), in 12 patients with IgM MGUS and in 30 healthy controls, of similar age and gender. Circulating VEGF, VEGF-A, bFGF, angiogenin, Ang-1 and Ang-2 were measured using ELISA method (R&D Systems, Minneapolis, MN, USA for VEGF, bFGF, angiogenin, Ang-1 and, Ang-2; Diaclone SAS, Besancon, France for VEGF-A). MVD was also evaluated in the BM biopsies of all patients, according to standard methodology. Table 1 depicts the levels of the studied angiogenic cytokines. The serum levels of VEGF, VEGFA, bFGF, angiogenin and Ang-2 were markedly elevated in WM patients compared to controls (p<0.001 for all comparisons); Ang-1 levels (p<0.01) were lower in WM patients than in controls, and the corresponding Ang-1 to Ang-2 ratio was significantly lower in WM patients than in controls, further indicating an angiogenic shift in WM patients. Circulating angiogenin (p<0.001) and Ang-2 (p=0.001) levels were also increased in WM patients compared to patients with IgM MGUS but Ang-1 levels were lower (p=0.003) resulting in Ang 1/2 ratio significantly higher in IgM MGUS than WM patients (p=0.004). In symptomatic WM patients, Ang-2 levels and the corresponding Ang-1/2 ratio correlated with serum beta2-microglobulin (r=0.454, p=0.002 and r=0.459, p=0.003, respectively). Ang-2 levels correlated with ISSWM stage (1914 ± 1175 pg/ml vs. 4461 ± 2628 pg/ml vs. 3926 ± 2172 pg/ml, for ISSWM-low, intermediate and high risk, respectively, p=0.007). A strong inverse correlation of MVD to Ang-1 was found in patients with WM (r=-0.600, p=0.011), indicative of the regulatory function of Ang-1 as an antagonist of vessel sprouting and new vessel formation. The median follow-up of symptomatic WM patients was 35 months. The median overall survival (OS) has not been reached yet, while the probability for 3-year OS was 76%. The median progression-free survival (PFS) was 57 months and the 3-year probability of PFS was 56%. Patients with Ang-2 levels above the median value had significantly shorter PFS (3-year PFS rate 82% vs. 50%, p=0.032; Figure). We conclude that in patients with WM, serum levels of several angiogenic cytokines (Ang-2, angiogenin, VEGF, VEGF-A, and bFGF) are markedly elevated and for some of these cytokines there is a correlation with disease features. The levels of pro-angiogenic cytokines, such as Ang-2 increase as disease evolves for IgM MGUS to symptomatic WM, while the Ang-1 decreases. We show that the MVD in the BM strongly correlates to decreasing Ang-1 levels, probably due to the decreasing inhibitory effect of Ang-1 to vessel formation in the BM microenvironment as disease evolves. For the first time we found that Ang-2, may also have a prognostic significance, associated with significantly shorter PFS. Further follow up is needed in order to evaluate the prognostic significance of Ang-2 for the OS of patients with WM Table: Levels of the studied circulating angiogenic cytokines (mean ± SD) Controls IgM MGUS aWM WM VEGF (pg/ml) 106 ± 76 323 ± 217 116 ± 83 399 ± 248 VEGF-A (pg/ml) 6.7 ± 13.6 97.5 ± 94 28.4 ± 49.3 113 ± 113 bFGF (pg/ml) 1.3 ± 3.2 12 ± 14 9.5 ± 16 17 ± 21.6 Angiogenin (pg/ml) 2.4×105 ± 0.5×105 2.7×105 ± 0.8×105 2.8×105 ± 0.7×105 4.5×105 ± 2.1×105 Ang-1 (pg/ml) 4.8×105 ± 1.1×105 4.8×105 ± 1.9×105 2.6×105 ± 1.5×105 2.5×105 ± 2.3×105 Ang-2 (pg/ml) 1747 ± 1023 1783 ± 684 3775 ± 1296 3424 ± 2570 Ang-1/2 ratio 28.1 ± 11.6 31 ± 14 6.5 ± 1.6 14.5 ± 17.7 Disclosures: No relevant conflicts of interest to declare.

Combination chemotherapy (M-2) protocol (BCNU, cyclophosphamide, vincristine, melphalan, and prednisone) for Waldenstrom macroglobulinemia: preliminary report

Blood ◽  
1982 ◽  
Vol 59 (5) ◽  
pp. 934-937 ◽  
Author(s):  
DC Jr Case
Keyword(s):  
Combination Chemotherapy ◽  
Response Rate ◽  
Waldenström’S Macroglobulinemia ◽  
Symptomatic Disease ◽  
Previously Treated ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Initiation Of Therapy ◽  
Waldenström's Macroglobulinemia

Abstract Fourteen consecutively referred, symptomatic patients with Waldenstrom's macroglobulinemia (ages 52–87 yr) have been treated with the 5-drug M-2 protocol (BCNU, cyclophosphamide, vincristine, melphalan, and prednisone). Three patients were previously treated and 11 patients were untreated. The majority of patients were symptomatic from hyperviscosity. All patients have responded to therapy. Two patients have achieved complete remissions and 12 patients partial remissions to date. None of the patients with symptomatic hyperviscosity has required plasmapheresis since therapy with the M-2 has been initiated. Lymphadenopathy, hepatosplenomegaly, and anemia have also responded to treatment. Follow-up data are limited, with survival from initiation of therapy with the M-2 ranging from 2+ to 35% mo (median 17+ mo) 2+-40+ mo from time of diagnosis). Combination chemotherapy for Waldenstrom's macroglobulinemia with the M-2 protocol appears to increase the response rate in patients with symptomatic disease. Further survival analysis will be carried out.

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