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      Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

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          Abstract

          The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.

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          A decade of immune-checkpoint inhibitors in cancer therapy

          Immunotherapy using immune-checkpoint modulators revolutionizes the oncology field far beyond their remarkable clinical efficacy in some patients. It creates radical changes in the evaluation of treatment efficacy and toxicity with a more holistic vision of the patient with cancer.
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            The bone marrow niche for haematopoietic stem cells.

            Niches are local tissue microenvironments that maintain and regulate stem cells. Haematopoiesis provides a model for understanding mammalian stem cells and their niches, but the haematopoietic stem cell (HSC) niche remains incompletely defined and beset by competing models. Recent progress has been made in elucidating the location and cellular components of the HSC niche in the bone marrow. The niche is perivascular, created partly by mesenchymal stromal cells and endothelial cells and often, but not always, located near trabecular bone. Outstanding questions concern the cellular complexity of the niche, the role of the endosteum and functional heterogeneity among perivascular microenvironments.
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              Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche.

              Multipotent stromal cells (MSCs) and their osteoblastic lineage cell (OBC) derivatives are part of the bone marrow (BM) niche and contribute to hematopoietic stem cell (HSC) maintenance. Here, we show that myeloproliferative neoplasia (MPN) progressively remodels the endosteal BM niche into a self-reinforcing leukemic niche that impairs normal hematopoiesis, favors leukemic stem cell (LSC) function, and contributes to BM fibrosis. We show that leukemic myeloid cells stimulate MSCs to overproduce functionally altered OBCs, which accumulate in the BM cavity as inflammatory myelofibrotic cells. We identify roles for thrombopoietin, CCL3, and direct cell-cell interactions in driving OBC expansion, and for changes in TGF-β, Notch, and inflammatory signaling in OBC remodeling. MPN-expanded OBCs, in turn, exhibit decreased expression of many HSC retention factors and severely compromised ability to maintain normal HSCs, but effectively support LSCs. Targeting this pathological interplay could represent a novel avenue for treatment of MPN-affected patients and prevention of myelofibrosis. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                14 February 2021
                February 2021
                : 22
                : 4
                : 1906
                Affiliations
                [1 ]Department of Laboratory Medicine and Pathology, Diagnostic Hematology and Clinical Genomics, AUSL/AOU Policlinico, 41124 Modena, Italy; g.riva@ 123456ausl.mo.it (G.R.); beatrice.lusenti@ 123456gmail.com (B.L.); enrico.tagliafico@ 123456unimore.it (E.T.); t.trenti@ 123456ausl.mo.it (T.T.)
                [2 ]Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, 41124 Modena, Italy; paolini.ambra@ 123456aou.mo.it (A.P.); fabio.forghieri@ 123456unimore.it (F.F.); maccaferri.monica@ 123456aou.mo.it (M.M.); messerotti.andrea@ 123456aou.mo.it (A.M.); pioli.valeria@ 123456aou.mo.it (V.P.); gilioli.andrea@ 123456aou.mo.it (A.G.); francesca.bettelli@ 123456unimore.it (F.B.); davide.giusti@ 123456unimore.it (D.G.); patrizia.barozzi@ 123456unimore.it (P.B.); ivana.lagreca@ 123456unimore.it (I.L.); rossana.maffei@ 123456unimore.it (R.M.); roberto.marasca@ 123456unimore.it (R.M.); leonardo.potenza@ 123456unimore.it (L.P.); mario.luppi@ 123456unimore.it (M.L.)
                [3 ]Institute of Pathology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, 41124 Modena, Italy; roncati.luca@ 123456aou.mo.it (L.R.); antonino.maiorana@ 123456unimore.it (A.M.)
                [4 ]Pediatric Hematology/Oncology Unit and Cell Factory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, 27100 Pavia, Italy; pcomoli@ 123456smatteo.pv.it
                [5 ]Centre for Regenerative Medicine “S. Ferrari”, University of Modena and Reggio Emilia, 41125 Modena, Italy; rossella.manfredini@ 123456unimore.it
                Author notes
                [* ]Correspondence: vincenzo.nasillo@ 123456unimore.it ; Tel.: +39-059-422-2173
                [†]

                Equally contributed as first author.

                [‡]

                Equally contributed as last author.

                Author information
                https://orcid.org/0000-0001-5122-5574
                https://orcid.org/0000-0003-2089-6230
                https://orcid.org/0000-0001-6949-2216
                https://orcid.org/0000-0001-9634-2520
                https://orcid.org/0000-0001-5819-3536
                https://orcid.org/0000-0003-0981-2542
                Article
                ijms-22-01906
                10.3390/ijms22041906
                7918142
                33672997
                3645dd62-dcde-48d1-b6d9-9f60adcb8b3c
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 15 January 2021
                : 08 February 2021
                Categories
                Review

                Molecular biology
                mpn,inflammation,immunity,t cells,niche,pv,et,pmf,jak2,calr
                Molecular biology
                mpn, inflammation, immunity, t cells, niche, pv, et, pmf, jak2, calr

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