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      OncoTargets and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the pathological basis of cancers, potential targets for therapy and treatment protocols to improve the management of cancer patients. Publishing high-quality, original research on molecular aspects of cancer, including the molecular diagnosis, since 2008. Sign up for email alerts here. 50,877 Monthly downloads/views I 4.345 Impact Factor I 7.0 CiteScore I 0.81 Source Normalized Impact per Paper (SNIP) I 0.811 Scimago Journal & Country Rank (SJR)

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      Is Open Access

      Essential Thrombocythaemia with Concomitant Waldenström Macroglobulinaemia: Case Report and Literature Review

      case-report

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Essential thrombocythaemia (ET) and Waldenström macroglobulinaemia (WM) are two distinct disorders. Studies have reported several cases of myeloproliferative neoplasms (MPNs) with concomitant plasma cell dyscrasia. However, there were no reported cases of ET with concomitant WM to date. Here, we present a 55-year-old Chinese man with thrombocytosis and raised immunoglobulin level. Further investigations led to a diagnosis of ET and coexistent WM. Next-generation sequencing (NGS) of his bone marrow identified 3 mutated genes: JAK2 V617F, MYD88 L265P, and ATM F1036L. After being treated with pegylated interferon and low-dose aspirin, his platelet count normalized and immunoglobulin M (IgM) level reduced. To the best of our knowledge, this is the first reported case of dual pathology ET with WM.

          Most cited references20

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          ATM activation by oxidative stress.

          The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.
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            MYD88 L265P somatic mutation in Waldenström's macroglobulinemia.

            Waldenström's macroglobulinemia is an incurable, IgM-secreting lymphoplasmacytic lymphoma (LPL). The underlying mutation in this disorder has not been delineated. We performed whole-genome sequencing of bone marrow LPL cells in 30 patients with Waldenström's macroglobulinemia, with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings in samples 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 Waldenström's macroglobulinemia, a somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-κB signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenström's 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 Waldenström's 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 IκBα and NF-κB p65 phosphorylation, as well as NF-κB nuclear staining, in Waldenström's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A 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 Waldenström's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2. MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating Waldenström's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.).
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              The microenvironment in mature B-cell malignancies: a target for new treatment strategies.

              Despite major therapeutic advances, most mature B-cell malignancies remain incurable. Compelling evidence suggests that crosstalk with accessory stromal cells in specialized tissue microenvironments, such as the bone marrow and secondary lymphoid organs, favors disease progression by promoting malignant B-cell growth and drug resistance. Therefore, disrupting the crosstalk between malignant B cells and their milieu is an attractive novel strategy for treating selected mature B-cell malignancies. Here we summarize the current knowledge about the cellular and molecular interactions between neoplastic B lymphocytes and accessory cells that shape a supportive microenvironment, and the potential therapeutic targets that are emerging, together with the new problems they raise. We discuss clinically relevant aspects and provide an outlook into future biologically oriented therapeutic strategies. We anticipate a paradigm shift in the treatment of selected B-cell malignancies, moving from targeting primarily the malignant cells toward combining cytotoxic drugs with agents that interfere with the microenvironment's proactive role. Such approaches hopefully will help eliminating residual disease, thereby improving our current therapeutic efforts.
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                Author and article information

                Journal
                Onco Targets Ther
                Onco Targets Ther
                OTT
                ott
                OncoTargets and therapy
                Dove
                1178-6930
                23 April 2020
                2020
                : 13
                : 3431-3435
                Affiliations
                [1 ]Department of Hematology, Taizhou Central Hospital (Taizhou University Hospital) , Taizhou, Zhejiang 318000, People’s Republic of China
                [2 ]Department of Hematology, Royal Marsden Hospital , London SW3 6JJ, UK
                [3 ]Department of Pathology, Taizhou Central Hospital (Taizhou University Hospital) , Taizhou, Zhejiang 318000, People’s Republic of China
                [4 ]Department of Laboratory Medicine, Taizhou Central Hospital (Taizhou University Hospital) , Taizhou, Zhejiang 318000, People’s Republic of China
                Author notes
                Correspondence: Linglong Xu Email daniongniong@163.com
                Author information
                http://orcid.org/0000-0002-1508-0301
                http://orcid.org/0000-0003-4496-6571
                Article
                245950
                10.2147/OTT.S245950
                7186880
                83a31a24-15f8-40c4-9ae7-3ee73c1f4b6d
                © 2020 Lu et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 14 January 2020
                : 09 April 2020
                Page count
                Figures: 2, References: 24, Pages: 5
                Categories
                Case Report

                Oncology & Radiotherapy
                myeloproliferative neoplasm,waldenström macroglobulinaemia,janus kinase 2,myeloid differentiation factor 88

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