Genetic Factors and Pathogenesis of Waldenström’s Macroglobulinemia

Monge, Jorge; Braggio, Esteban; Ansell, Stephen M.

doi:10.1007/s11912-013-0331-7

Cited by 12 publications

(4 citation statements)

References 73 publications

(95 reference statements)

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“…In these cases, Waldenstrom disease, colorectal cancer, thyroid carcinoma and colorectal polyposis occurred despite not being associated with any of the relevant MINAS CSGs [ 21 – 24 ]. Each of these cases presented with multiple primary tumours and rare CSG combinations so it is not possible to say whether this was a manifestation of synergy between the relevant CSGs or coincidental (and the presence of multiple tumours of unusual types might have been more likely to prompt genetic testing).…”

Section: Phenotypic Consequences Of Minasmentioning

confidence: 99%

Multilocus Inherited Neoplasia Allele Syndrome (MINAS): an update

et al. 2022

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Multi-locus Inherited Neoplasia Allele Syndrome (MINAS) refers to individuals with germline pathogenic variants in two or more cancer susceptibility genes(CSGs). With increased use of exome/genome sequencing it would be predicted that detection of MINAS would become more frequent. Here we review recent progress in knowledge of MINAS. A systematic literature search for reports of individuals with germline pathogenic variants in 2 or more of 94 CSGs was performed. In addition, participants with multiple primary tumours who underwent genome sequencing as part of the Rare Disease arm of the UK 100,000 Genomes Project were interrogated to detect additional cases. We identified 385 MINAS cases (211 reported in the last 5 years, 6 from 100,000 genomes participants). Most (287/385) cases contained at least one pathogenic variant in either BRCA1 or BRCA2. 108/385 MINAS cases had multiple primary tumours at presentation and a subset of cases presented unusual multiple tumour phenotypes. We conclude that, as predicted, increasing numbers of individuals with MINAS are being have been reported but, except for individuals with BRCA1/BRCA2 MINAS, individual CSG combinations are generally rare. In many cases it appears that the clinical phenotype is that which would be expected from the effects of the constituent CSG variants acting independently. However, in some instances the presence of unusual tumour phenotypes and/or multiple primary tumours suggests that there may be complex interactions between the relevant MINAS CSGs. Systematic reporting of MINAS cases in a MINAS database (e.g. https://databases.lovd.nl/shared/diseases/04296) will facilitate more accurate prognostic predictions for specific CSG combinations.

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Section: Phenotypic Consequences Of Minasmentioning

confidence: 99%

Multilocus Inherited Neoplasia Allele Syndrome (MINAS): an update

et al. 2022

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“…Waldenstrom macroglobulinemia (WM) is an uncommon low-grade B-cell lymphoma characterized by a lymphoplasmacytic infiltrate within the bone marrow (BM) and by increased synthesis and accumulation of monoclonal immunoglobulin M (IgM) in the serum, which increases the risk of hyperviscosity in the affected patients. 1,2 Despite advancements in understanding the biology of WM 3 and introduction of novel therapeutic interventions, 4 the disease still remains incurable. Recent studies indicate that the underlying molecular mechanisms contributing to the pathogenesis of WM are attributed not only to the genomic aberrations of malignant cells 5 but also to the complex signaling events arising from the interaction of malignant cells with the components of BM milieu.…”

Section: Introductionmentioning

confidence: 99%

Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia

et al. 2018

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Although immune checkpoint molecules regulate the progression of certain cancers, their significance in malignant development of Waldenstrom macroglobulinemia (WM), an incurable low-grade B-cell lymphoma, remains unknown. Recently, cytokines in the bone marrow (BM) microenvironment are shown to contribute to the pathobiology of WM. Here, we investigated the impact of cytokines, including interleukin-6 (IL-6) and IL-21, on immune regulation and particularly on the programmed death-1 (PD-1) and its ligands PD-L1 and PD-L2. We showed that IL-21, interferon γ, and IL-6 significantly induced PD-L1 and PD-L2 gene expression in WM cell lines. Increased PD-L1 and PD-L2 messenger RNA was also detected in patients' BM cells. Patients' nonmalignant BM cells, including T cells and monocytes, showed increased PD-L1, but minimal or undetectable PD-L2 surface expression. There was also very modest PD-L1 and PD-L2 surface expression by malignant WM cells, suggesting that ligands are cleaved from the cell surface. Levels of soluble ligands were higher in patients' BM plasma and blood serum than controls. Furthermore, IL-21 and IL-6 increased secreted PD-L1 in the culture media of WM cell lines, implying that elevated levels of soluble PD-1 ligands are cytokine mediated. Soluble PD-1 ligands reduced T-cell proliferation, phosphorylated extracellular signal-regulated kinase and cyclin A levels, mitochondrial adenosine triphosphate production, and spare respiratory capacity. In conclusion, we identify that soluble PD-1 ligands are elevated in WM patients and, in addition to surface-bound ligands in WM BM, could regulate T-cell function. Given the capability of secreted forms to be bioactive at distant sites, soluble PD-1 ligands have the potential to promote disease progression in WM.

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“…There are 0.38 incidents in every 100,000 population per year. With aging, it increases to 2.85 in patients above 80 years of age 4. Among patients of all ages, males are more likely to be affected; the disease has a higher incidence rate in the United States than in other countries 5.…”

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confidence: 99%

“…With aging, it increases to 2.85 in patients above 80 years of age. 4 Among patients of all ages, males are more likely to be affected; the disease has a higher incidence rate in the United States than in other countries. 5 There is an increased prevalence of both solid tumors and hematological malignancies in patients.…”

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confidence: 99%

Pharmacokinetics-Pharmacodynamics Modeling and Evaluation of Tumor Response to Bortezomib Proteasome Inhibitor in Waldenstrom Macroglobulinemia

Munir¹,

Fazal²,

Bhatti³

et al. 2023

American Journal of Clinical Oncology

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Background: Waldenstrom's macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is a type of non-Hodgkin's lymphoma in which the malignant cells produce many macroglobulin proteins. It originates from B cells and develops in the bone marrow, where Wm cells combine to produce distinct types of blood cells, resulting in reduced volumes of red blood cells, white blood cells, and platelets, making it harder for the body to fight diseases. Chemoimmunotherapy is being used for the clinical management of WM, but new targeted agents, the BTK inhibitor ibrutinib and the proteasome inhibitor bortezomib, have shown significant improvements in patients with relapsed/refractory WM. However, given its effectiveness, drug resistance and relapse are normal, and there is little research on the pathways responsible for drug effects on the tumor.Methods: In this study, Pharmacokinetics-pharmacodynamic simulations were done to assess the effect of the proteasome inhibitor bortezomib on the tumor. For this purpose, the Pharmacokineticspharmacodynamic model was developed. The model parameters were determined and calculated using the Ordinary Differential Equation solver toolbox and the least-squares function. Pharmacokinetic profiles and pharmacodynamic analysis were performed to determine the change in tumor weight associated with the use of proteasome inhibitors.Results: Bortezomib and ixazomib have been found to reduce tumor weight briefly, but once the dose is reduced, the tumor begins to grow again. Carfilzomib and oprozomib had better results, and rituximab reduced tumor weight more effectively. Conclusion:Once validated, it is proposed that a combination of selected drugs can be evaluated in the laboratory to treat WM.

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Genetic Factors and Pathogenesis of Waldenström’s Macroglobulinemia

Cited by 12 publications

References 73 publications

Multilocus Inherited Neoplasia Allele Syndrome (MINAS): an update

Multilocus Inherited Neoplasia Allele Syndrome (MINAS): an update

Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia

Pharmacokinetics-Pharmacodynamics Modeling and Evaluation of Tumor Response to Bortezomib Proteasome Inhibitor in Waldenstrom Macroglobulinemia

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