{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T00:14:59Z","timestamp":1778976899278,"version":"3.51.4"},"reference-count":96,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T00:00:00Z","timestamp":1697673600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health (Ricerca Corrente N701A (F. Fais))"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in Western countries. Although characterized by the progressive expansion and accumulation of leukemic B cells in peripheral blood, CLL cells develop in protective niches mainly located within lymph nodes and bone marrow. Multiple interactions between CLL and microenvironmental cells may favor the expansion of a B cell clone, further driving immune cells toward an immunosuppressive phenotype. Here, we summarize the current understanding of bone tissue alterations in CLL patients, further addressing and suggesting how the multiple interactions between CLL cells and osteoblasts\/osteoclasts can be involved in these processes. Recent findings proposing the disruption of the endosteal niche by the expansion of a leukemic B cell clone appear to be a novel field of research to be deeply investigated and potentially relevant to provide new therapeutic approaches.<\/jats:p>","DOI":"10.3390\/cancers15205058","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T11:46:26Z","timestamp":1697715986000},"page":"5058","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Unraveling the Bone Tissue Microenvironment in Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7206-376X","authenticated-orcid":false,"given":"Paolo","family":"Giannoni","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, Biology Section, University of Genova, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecilia","family":"Marini","sequence":"additional","affiliation":[{"name":"Nuclear Medicine Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"},{"name":"CNR Institute of Bioimages and Molecular Physiology, 20054 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3335-1101","authenticated-orcid":false,"given":"Giovanna","family":"Cutrona","sequence":"additional","affiliation":[{"name":"Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gian Mario","family":"Sambuceti","sequence":"additional","affiliation":[{"name":"Nuclear Medicine Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"},{"name":"Department of Health Sciences, University of Genova, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franco","family":"Fais","sequence":"additional","affiliation":[{"name":"Molecular Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"},{"name":"Department of Experimental Medicine, Anatomy Section, University of Genova, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8481-7848","authenticated-orcid":false,"given":"Daniela","family":"de Totero","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Genova, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1056\/NEJMra041720","article-title":"Chronic lymphocytic leukemia","volume":"352","author":"Chiorazzi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16096","DOI":"10.1038\/nrdp.2016.96","article-title":"Chronic lymphocytic leukaemia","volume":"3","author":"Kipps","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1182\/blood-2017-10-764373","article-title":"Chronic lymphocytic leukemia and mantle cell lymphoma: Crossroads of genetic and microenvironment interactions","volume":"131","author":"Puente","year":"2018","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e143764","DOI":"10.1172\/JCI143764","article-title":"Exploiting bone niches: Progression of disseminated tumor cells to metastasis","volume":"131","author":"Muscarella","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1038\/nrrheum.2017.213","article-title":"Updating osteoimmunology: Regulation of bone cells by innate and adaptive immunity","volume":"14","author":"Walsh","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14159","DOI":"10.1038\/s41598-017-12761-1","article-title":"Functional Activation of Osteoclast Commitment in Chronic Lymphocytic Leukaemia: A Possible Role for RANK\/RANKL Pathway","volume":"7","author":"Marini","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.3324\/haematol.2019.231456","article-title":"Chronic lymphocytic leukemia cells impair osteoblastogenesis and promote osteoclastogenesis: Role of TNFalpha, IL-6 and IL-11 cytokines","volume":"106","author":"Giannoni","year":"2021","journal-title":"Haematologica"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Giannoni, P., Marini, C., Cutrona, G., Todoerti, K., Neri, A., Ibatici, A., Sambuceti, G., Pigozzi, S., Mora, M., and Ferrarini, M. (2022). A High Percentage of CD16+ Monocytes Correlates with the Extent of Bone Erosion in Chronic Lymphocytic Leukemia Patients: The Impact of Leukemic B Cells in Monocyte Differentiation and Osteoclast Maturation. Cancers, 14.","DOI":"10.21203\/rs.3.rs-1784147\/v1"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1126\/science.289.5484.1504","article-title":"Bone resorption by osteoclasts","volume":"289","author":"Teitelbaum","year":"2000","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1089\/ten.teb.2016.0454","article-title":"Osteoblast Differentiation and Bone Matrix Formation In Vivo and In Vitro","volume":"23","author":"Blair","year":"2017","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kim, J.S., Choi, M., Choi, J.Y., Kim, J.Y., Kim, J.Y., Song, J.S., Ivashkiv, L.B., and Lee, E.Y. (2020). Implication of the Association of Fibrinogen Citrullination and Osteoclastogenesis in Bone Destruction in Rheumatoid Arthritis. Cells, 9.","DOI":"10.3390\/cells9122720"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"706","DOI":"10.14348\/molcells.2017.0225","article-title":"Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation","volume":"40","author":"Park","year":"2017","journal-title":"Mol. Cells"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/nm.2448","article-title":"Matrix-embedded cells control osteoclast formation","volume":"17","author":"Xiong","year":"2011","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3597","DOI":"10.1073\/pnas.95.7.3597","article-title":"Osteoclast differentiation factor is a ligand for osteoprotegerin\/osteoclastogenesis-inhibitory factor and is identical to TRANCE\/RANKL","volume":"95","author":"Yasuda","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1073\/pnas.97.4.1566","article-title":"RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism","volume":"97","author":"Li","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S1534-5807(02)00369-6","article-title":"Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts","volume":"3","author":"Takayanagi","year":"2002","journal-title":"Dev. Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1222129","DOI":"10.3389\/fimmu.2023.1222129","article-title":"The effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: A review","volume":"14","author":"Xu","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"116540","DOI":"10.1016\/j.bone.2022.116540","article-title":"Cytokine-mediated immunomodulation of osteoclastogenesis","volume":"164","author":"Zhou","year":"2022","journal-title":"Bone"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.3389\/fimmu.2019.02182","article-title":"Chemokines in Physiological and Pathological Bone Remodeling","volume":"10","author":"Brylka","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e05379","DOI":"10.1002\/ccr3.5379","article-title":"A case of bone lesion in a patient with relapsed chronic lymphocytic leukemia and review of the literature","volume":"10","author":"Bacchiarri","year":"2022","journal-title":"Clin. Case Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1148\/radiol.14131944","article-title":"Adult advanced chronic lymphocytic leukemia: Computational analysis of whole-body CT documents a bone structure alteration","volume":"271","author":"Fiz","year":"2014","journal-title":"Radiology"},{"key":"ref_22","first-page":"323","article-title":"Osteoclast cytomorphometry and scanning electron microscopy of bone eroded surfaces during leukemic disorders","volume":"4","author":"Chappard","year":"1990","journal-title":"Scanning Microsc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/j.1365-2141.1990.tb07902.x","article-title":"Micro-osteoclast resorption as a characteristic feature of B-cell malignancies other than multiple myeloma","volume":"76","author":"Rossi","year":"1990","journal-title":"Br. J. Haematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/BF02555791","article-title":"Osteoclast cytomorphometry demonstrates an abnormal population in B cell malignancies but not in multiple myeloma","volume":"48","author":"Chappard","year":"1991","journal-title":"Calcif. Tissue Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1158\/0008-5472.CAN-12-2280","article-title":"RANKL expression, function, and therapeutic targeting in multiple myeloma and chronic lymphocytic leukemia","volume":"73","author":"Schmiedel","year":"2013","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2468","DOI":"10.3109\/10428194.2016.1151506","article-title":"Soluble RANKL production by leukemic cells in a case of chronic lymphocytic leukemia with bone destruction","volume":"57","author":"Borge","year":"2016","journal-title":"Leuk. Lymphoma"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e20200517","DOI":"10.1084\/jem.20200517","article-title":"Pathological RANK signaling in B cells drives autoimmunity and chronic lymphocytic leukemia","volume":"218","author":"Alankus","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/bonekey.2012.59","article-title":"Osteoimmunology: The expanding role of immunoreceptors in osteoclasts and bone remodeling","volume":"1","author":"Long","year":"2012","journal-title":"Bonekey Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1016\/j.bbagen.2013.12.013","article-title":"Effect of TNFalpha on osteoblastogenesis from mesenchymal stem cells","volume":"1840","author":"Kotake","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2791","DOI":"10.1073\/pnas.050574297","article-title":"Expression and function of wingless and frizzled homologs in rheumatoid arthritis","volume":"97","author":"Sen","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1182\/blood.V99.5.1610","article-title":"Bone marrow progenitor cell reserve and function and stromal cell function are defective in rheumatoid arthritis: Evidence for a tumor necrosis factor alpha-mediated effect","volume":"99","author":"Papadaki","year":"2002","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e8","DOI":"10.4110\/in.2018.18.e8","article-title":"Regulation of Osteoclast Differentiation by Cytokine Networks","volume":"18","author":"Amarasekara","year":"2018","journal-title":"Immune Netw."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"788","DOI":"10.3389\/fendo.2018.00788","article-title":"Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma","volume":"9","author":"Harmer","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"155655","DOI":"10.1016\/j.cyto.2021.155655","article-title":"Influences of the IL-6 cytokine family on bone structure and function","volume":"146","author":"Sims","year":"2021","journal-title":"Cytokine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1182\/blood.V76.2.393.bloodjournal762393","article-title":"Production of tumor necrosis factor-alpha by B-cell chronic lymphocytic leukemia cells: A possible regulatory role of TNF in the progression of the disease","volume":"76","author":"Foa","year":"1990","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1182\/blood.V100.4.1215.h81602001215_1215_1219","article-title":"The clinical significance of tumor necrosis factor-alpha plasma level in patients having chronic lymphocytic leukemia","volume":"100","author":"Ferrajoli","year":"2002","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.semcancer.2010.09.005","article-title":"Chemokines and chemokine receptors in chronic lymphocytic leukemia (CLL): From understanding the basics towards therapeutic targeting","volume":"20","author":"Burger","year":"2010","journal-title":"Semin. Cancer Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3","DOI":"10.13055\/ojhmt_3_S1_03.120221","article-title":"Cell Trafficking in Chronic Lymphocytic Leukemia","volume":"3","author":"Davids","year":"2012","journal-title":"Open J. Hematol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s00277-009-0876-6","article-title":"The role of chemokines in B cell chronic lymphocytic leukaemia: Pathophysiological aspects and clinical impact","volume":"89","author":"Schrottner","year":"2010","journal-title":"Ann. Hematol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.3324\/haematol.2016.142679","article-title":"Chronic lymphocytic leukemia cells are active participants in microenvironmental cross-talk","volume":"102","author":"Eldering","year":"2017","journal-title":"Haematologica"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1002\/1521-4141(200205)32:5<1403::AID-IMMU1403>3.0.CO;2-Y","article-title":"Chronic lymphocytic leukemia B cells are endowed with the capacity to attract CD4+, CD40L+ T cells by producing CCL22","volume":"32","author":"Ghia","year":"2002","journal-title":"Eur. J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1038\/leu.2011.149","article-title":"The functional in vitro response to CD40 ligation reflects a different clinical outcome in patients with chronic lymphocytic leukemia","volume":"25","author":"Scielzo","year":"2011","journal-title":"Leukemia"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"De Cecco, L., Capaia, M., Zupo, S., Cutrona, G., Matis, S., Brizzolara, A., Orengo, A.M., Croce, M., Marchesi, E., and Ferrarini, M. (2015). Interleukin 21 Controls mRNA and MicroRNA Expression in CD40-Activated Chronic Lymphocytic Leukemia Cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134706"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/164_2020_349","article-title":"Chemokines and Bone","volume":"262","author":"Gilchrist","year":"2020","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.2147\/CIA.S254885","article-title":"Increased Osteoblastic Cxcl9 Contributes to the Uncoupled Bone Formation and Resorption in Postmenopausal Osteoporosis","volume":"15","author":"Liu","year":"2020","journal-title":"Clin. Interv. Aging."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1002\/jbmr.4646","article-title":"CXCL9 Predicts the Risk of Osteoporotic Hip Fracture in a Prospective Cohort of Chinese Men-A Matched Case-Control Study","volume":"37","author":"Phan","year":"2022","journal-title":"J. Bone Miner. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5201","DOI":"10.1182\/blood-2011-03-342436","article-title":"Identification of outcome-correlated cytokine clusters in chronic lymphocytic leukemia","volume":"118","author":"Yan","year":"2011","journal-title":"Blood"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.18632\/oncotarget.6465","article-title":"Ulocuplumab (BMS-936564 \/ MDX1338): A fully human anti-CXCR4 antibody induces cell death in chronic lymphocytic leukemia mediated through a reactive oxygen species-dependent pathway","volume":"7","author":"Kashyap","year":"2016","journal-title":"Oncotarget"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2655","DOI":"10.1182\/blood.V96.8.2655","article-title":"Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1","volume":"96","author":"Burger","year":"2000","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1182\/blood.V99.3.1030","article-title":"Distinctive features of \u201cnurselike\u201d cells that differentiate in the context of chronic lymphocytic leukemia","volume":"99","author":"Tsukada","year":"2002","journal-title":"Blood"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Fiorcari, S., Maffei, R., Atene, C.G., Potenza, L., Luppi, M., and Marasca, R. (2021). Nurse-Like Cells and Chronic Lymphocytic Leukemia B Cells: A Mutualistic Crosstalk inside Tissue Microenvironments. Cells, 10.","DOI":"10.3390\/cells10020217"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Mesaros, O., Jimbu, L., Neaga, A., Popescu, C., Berceanu, I., Tomuleasa, C., Fetica, B., and Zdrenghea, M. (2020). Macrophage Polarization in Chronic Lymphocytic Leukemia: Nurse-Like Cells Are the Caretakers of Leukemic Cells. Biomedicines, 8.","DOI":"10.3390\/biomedicines8110516"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3324\/haematol.2013.091405","article-title":"Chronic Lymphocytic Leukemia Nurse-like cells express the hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages","volume":"99","author":"Giannoni","year":"2014","journal-title":"Haematologica"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1182\/blood-2014-07-589069","article-title":"Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia","volume":"125","author":"Audrito","year":"2015","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/j.1365-2141.2011.08747.x","article-title":"Nurse-like cells show deregulated expression of genes involved in immunocompetence","volume":"154","author":"Bhattacharya","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.bcmd.2012.12.003","article-title":"Circulating microenvironment of CLL: Are nurse-like cells related to tumor-associated macrophages?","volume":"50","author":"Filip","year":"2013","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/nrc2639","article-title":"Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: Can we see the wood for the trees?","volume":"9","author":"Lob","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1182\/bloodadvances.2016000984","article-title":"Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment","volume":"1","author":"Serra","year":"2016","journal-title":"Blood Adv."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1182\/blood-2013-12-546416","article-title":"CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs","volume":"124","author":"Jitschin","year":"2014","journal-title":"Blood"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Zarobkiewicz, M., Kowalska, W., Chocholska, S., Tomczak, W., Szymanska, A., Morawska, I., Wojciechowska, A., and Bojarska-Junak, A. (2020). High M-MDSC Percentage as a Negative Prognostic Factor in Chronic Lymphocytic Leukaemia. Cancers, 12.","DOI":"10.3390\/cancers12092614"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.clml.2012.06.001","article-title":"Indoleamine 2,3-dioxygenase activity and expression in patients with chronic lymphocytic leukemia","volume":"12","author":"Lindstrom","year":"2012","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.3324\/haematol.2012.073080","article-title":"The monocytic population in chronic lymphocytic leukemia shows altered composition and deregulation of genes involved in phagocytosis and inflammation","volume":"98","author":"Maffei","year":"2013","journal-title":"Haematologica"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"17","DOI":"10.5603\/FHC.a2020.0002","article-title":"Expression of CD163 and HLA-DR molecules on the monocytes in chronic lymphocytic leukemia patients","volume":"58","author":"Kowalska","year":"2020","journal-title":"Folia Histochem. Cytobiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"773","DOI":"10.3324\/haematol.2016.153841","article-title":"IL21R expressing CD14(+)CD16(+) monocytes expand in multiple myeloma patients leading to increased osteoclasts","volume":"102","author":"Bolzoni","year":"2017","journal-title":"Haematologica"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/j.cell.2007.12.037","article-title":"Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals","volume":"132","author":"Shinohara","year":"2008","journal-title":"Cell"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"23033","DOI":"10.1002\/jcp.28863","article-title":"Modulation of macrophage subtypes by IRF5 determines osteoclastogenic potential","volume":"234","author":"Yang","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"R14","DOI":"10.1186\/ar2915","article-title":"CD16 (FcRgammaIII) as a potential marker of osteoclast precursors in psoriatic arthritis","volume":"12","author":"Chiu","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.4161\/onci.21990","article-title":"Myeloid-derived suppressor cells expand during breast cancer progression and promote tumor-induced bone destruction","volume":"1","author":"Danilin","year":"2012","journal-title":"Oncoimmunology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1080\/08820139.2018.1552360","article-title":"Myeloid-Derived Suppressor Cells at the Intersection of Inflammaging and Bone Fragility","volume":"47","author":"Kirkwood","year":"2018","journal-title":"Immunol. Investig."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1158\/0008-5472.CAN-12-2202","article-title":"Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer","volume":"73","author":"Sawant","year":"2013","journal-title":"Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4606","DOI":"10.1158\/0008-5472.CAN-13-0305","article-title":"Myeloid-derived suppressor cells as osteoclast progenitors: A novel target for controlling osteolytic bone metastasis","volume":"73","author":"Sawant","year":"2013","journal-title":"Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"568362","DOI":"10.3389\/fimmu.2020.568362","article-title":"The Immunoregulatory Role of Myeloid-Derived Suppressor Cells in the Pathogenesis of Rheumatoid Arthritis","volume":"11","author":"Yan","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Zhuang, J., Zhang, J., Lwin, S.T., Edwards, J.R., Edwards, C.M., Mundy, G.R., and Yang, X. (2012). Osteoclasts in multiple myeloma are derived from Gr-1+CD11b+myeloid-derived suppressor cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048871"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/jcb.24952","article-title":"The bone marrow endosteal niche: How far from the surface?","volume":"116","author":"Taichman","year":"2015","journal-title":"J. Cell Biochem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.canlet.2012.08.012","article-title":"Targeting the microenvironment in chronic lymphocytic leukemia offers novel therapeutic options","volume":"328","author":"Audrito","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s00109-021-02164-1","article-title":"Bone marrow adiposity during pathologic bone loss: Molecular mechanisms underlying the cellular events","volume":"100","author":"Li","year":"2022","journal-title":"J. Mol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1002\/iub.1254","article-title":"The impact of bone marrow adipocytes on osteoblast and osteoclast differentiation","volume":"66","author":"Muruganandan","year":"2014","journal-title":"IUBMB Life"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1056\/NEJMoa0808718","article-title":"Cold-activated brown adipose tissue in healthy men","volume":"360","author":"Vanhommerig","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/ncprheum0070","article-title":"Mechanisms of disease: Is osteoporosis the obesity of bone?","volume":"2","author":"Rosen","year":"2006","journal-title":"Nat. Clin. Pract. Rheumatol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"eaau9087","DOI":"10.1126\/scitranslmed.aau9087","article-title":"Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease","volume":"11","author":"Liu","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1002\/hon.3144","article-title":"Functional consequences of inhibition of Bruton\u2019s tyrosine kinase by ibrutinib in chronic lymphocytic leukemia","volume":"41","author":"Chen","year":"2023","journal-title":"Hematol. Oncol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1080\/10428194.2022.2064995","article-title":"The role of BTK inhibitors on the tumor microenvironment in CLL","volume":"63","author":"McCay","year":"2022","journal-title":"Leuk. Lymphoma"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Zhu, S., Gokhale, S., Jung, J., Spirollari, E., Tsai, J., Arceo, J., Wu, B.W., Victor, E., and Xie, P. (2021). Multifaceted Immunomodulatory Effects of the BTK Inhibitors Ibrutinib and Acalabrutinib on Different Immune Cell Subsets\u2014Beyond B Lymphocytes. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.727531"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"962552","DOI":"10.3389\/fimmu.2022.962552","article-title":"Effects of ibrutinib on T-cell immunity in patients with chronic lymphocytic leukemia","volume":"13","author":"Liu","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Mhibik, M., Wiestner, A., and Sun, C. (2019). Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010068"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1038\/leu.2017.304","article-title":"Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1\/PD-L1 pathway","volume":"32","author":"Kondo","year":"2018","journal-title":"Leukemia"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.bone.2013.11.025","article-title":"The orally available Btk inhibitor ibrutinib (PCI-32765) protects against osteoclast-mediated bone loss","volume":"60","author":"Shinohara","year":"2014","journal-title":"Bone"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2476","DOI":"10.3109\/10428194.2016.1151510","article-title":"Osteolytic lesions occur rarely in patients with B-CLL and may respond well to ibrutinib","volume":"57","author":"Shumilov","year":"2016","journal-title":"Leuk. Lymphoma"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1158\/1078-0432.CCR-15-1965","article-title":"Disruption of in vivo Chronic Lymphocytic Leukemia Tumor-Microenvironment Interactions by Ibrutinib--Findings from an Investigator-Initiated Phase II Study","volume":"22","author":"Niemann","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"65968","DOI":"10.18632\/oncotarget.11782","article-title":"Ibrutinib modifies the function of monocyte\/macrophage population in chronic lymphocytic leukemia","volume":"7","author":"Fiorcari","year":"2016","journal-title":"Oncotarget"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e355","DOI":"10.1038\/bcj.2015.74","article-title":"Nurse-like cells mediate ibrutinib resistance in chronic lymphocytic leukemia patients","volume":"5","author":"Boissard","year":"2015","journal-title":"Blood Cancer J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.4049\/jimmunol.2100931","article-title":"Disruption of Nurse-like Cell Differentiation as a Therapeutic Strategy for Chronic Lymphocytic Leukemia","volume":"209","author":"Santhanam","year":"2022","journal-title":"J. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"106520","DOI":"10.1016\/j.leukres.2021.106520","article-title":"Impact of long-term ibrutinib treatment on circulating immune cells in previously untreated chronic lymphocytic leukemia","volume":"102","author":"Solman","year":"2021","journal-title":"Leuk. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"100201","DOI":"10.1016\/j.bonr.2019.100201","article-title":"Bruton\u2019s tyrosine kinase (Btk) inhibitor tirabrutinib suppresses osteoclastic bone resorption","volume":"10","author":"Ariza","year":"2019","journal-title":"Bone Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1002\/JPER.18-0334","article-title":"A novel Bruton\u2019s tyrosine kinase inhibitor, acalabrutinib, suppresses osteoclast differentiation and Porphyromonas gingivalis lipopolysaccharide-induced alveolar bone resorption","volume":"90","author":"Pokhrel","year":"2019","journal-title":"J. Periodontol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1007\/s12272-019-01163-8","article-title":"Idelalisib inhibits osteoclast differentiation and pre-osteoclast migration by blocking the PI3Kdelta-Akt-c-Fos\/NFATc1 signaling cascade","volume":"42","author":"Yeon","year":"2019","journal-title":"Arch. Pharm. 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