{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:14:57Z","timestamp":1790799297921,"version":"4.1.0"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T00:00:00Z","timestamp":1688428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["428858226 417911533"],"award-info":[{"award-number":["428858226 417911533"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009398","name":"Medizinische Fakult\u00e4t, RWTH Aachen University","doi-asserted-by":"publisher","award":["O3-5\/531805"],"award-info":[{"award-number":["O3-5\/531805"]}],"id":[{"id":"10.13039\/501100009398","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The management of patients with chronic myeloid leukemia (CML) has been revolutionized by the introduction of tyrosine kinase inhibitors (TKIs), which induce deep molecular responses so that treatment can eventually be discontinued, leading to treatment-free remission (TFR) in a subset of patients. Unfortunately, leukemic stem cells (LSCs) often persist and a fraction of these can again expand in about half of patients that attempt TKI discontinuation. In this study, we show that presence of myelofibrosis (MF) at the time of diagnosis is a factor associating with TFR failure. Fibrotic transformation is governed by the action of several cytokines, and interestingly, some of them have also been described to support LSC persistence. At the cellular level, these could be produced by both malignant cells and by components of the bone marrow (BM) niche, including megakaryocytes (MKs) and mesenchymal stromal cells (MSCs). In our cohort of 57 patients, around 40% presented with MF at diagnosis and the number of blasts in the peripheral blood and BM was significantly elevated in patients with higher grade of MF. Employing a CML transgenic mouse model, we could observe higher levels of alpha-smooth muscle actin (\u03b1-SMA) in the BM when compared to control mice. Short-term treatment with the TKI nilotinib, efficiently reduced spleen weight and <jats:italic>BCR::ABL1<\/jats:italic> mRNA levels, while \u03b1-SMA expression was only partially reduced. Interestingly, the number of MKs was increased in the spleen of CML mice and elevated in both BM and spleen upon nilotinib treatment. Analysis of human CML-vs healthy donor (HD)-derived MSCs showed an altered expression of gene signatures reflecting fibrosis as well as hematopoietic support, thus suggesting MSCs as a potential player in these two processes. Finally, in our cohort, 12 patients qualified for TKI discontinuation, and here we observed that all patients who failed TFR had BM fibrosis at diagnosis, whereas this was only the case in 25% of patients with achieved TFR, further supporting the link between fibrosis and LSC persistence.<\/jats:p>","DOI":"10.3389\/fphar.2023.1212392","type":"journal-article","created":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T06:38:45Z","timestamp":1688452725000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients"],"prefix":"10.3389","volume":"14","author":[{"given":"Henrike","family":"Jacobi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Vieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlena","family":"B\u00fctow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina Y.","family":"Namasu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Fl\u00fcter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan G.","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago","family":"Mai\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Lindemann-Docter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Chatain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Beier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Huber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Crysandt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim H.","family":"Br\u00fcmmendorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirle","family":"Schemionek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/j.stem.2019.02.018","article-title":"Mesenchymal niche-specific expression of Cxcl12 controls quiescence of treatment-resistant leukemia stem cells","volume":"24","author":"Agarwal","year":"2019","journal-title":"Cell Stem Cell"},{"key":"B2","doi-asserted-by":"publisher","first-page":"109386","DOI":"10.1016\/j.celrep.2021.109386","article-title":"TNF-\u03b1-induced alterations in stromal progenitors enhance leukemic stem cell growth via CXCR2 signaling","volume":"36","author":"Agarwal","year":"2021","journal-title":"Cell Rep."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1182\/blood.v85.5.1306.bloodjournal8551306","article-title":"Long-term culture of chronic myelogenous leukemia marrow cells on stem cell factor-deficient stroma favors benign progenitors","volume":"85","author":"Agarwal","year":"1995","journal-title":"Blood"},{"key":"B4","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.leukres.2017.07.007","article-title":"Bone marrow mesenchymal stromal cell (MSC) gene profiling in chronic myeloid leukemia (CML) patients at diagnosis and in deep molecular response induced by tyrosine kinase inhibitors (TKIs)","volume":"60","author":"Aggoune","year":"2017","journal-title":"Leuk. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1007\/s11899-021-00653-1","article-title":"Treatment-free remission: The new goal in CML therapy","volume":"16","author":"Atallah","year":"2021","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"B6","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1182\/blood.v99.1.381","article-title":"Treatment of chronic myelogenous leukemia with the tyrosine kinase inhibitor STI571 results in marked regression of bone marrow fibrosis","volume":"99","author":"Beham-Schmid","year":"2002","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","first-page":"752","DOI":"10.12688\/f1000research.8190.1","article-title":"The myofibroblast in wound healing and fibrosis: Answered and unanswered questions","volume":"5","author":"Bochaton-Piallat","year":"2016","journal-title":"F1000Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1038\/nm.3707","article-title":"Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion","volume":"20","author":"Bruns","year":"2014","journal-title":"Nat. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1038\/sj.leu.2403451","article-title":"Treatment intensity significantly influencing fibrosis in bone marrow independently of the cytogenetic response: meta-analysis of the long-term results from two prospective controlled trials on chronic myeloid leukemia","volume":"18","author":"Buesche","year":"2004","journal-title":"Leukemia"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2420","DOI":"10.1038\/sj.leu.2404917","article-title":"Marrow fibrosis and its relevance during imatinib treatment of chronic myeloid leukemia","volume":"21","author":"Buesche","year":"2007","journal-title":"Leukemia"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2444","DOI":"10.1038\/sj.leu.2403172","article-title":"Marrow fibrosis, indicator of therapy failure in chronic myeloid leukemia - prospective long-term results from a randomized-controlled trial","volume":"17","author":"Buesche","year":"2003","journal-title":"Leukemia"},{"key":"B13","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1002\/cncr.20380","article-title":"Imatinib mesylate therapy reduces bone marrow fibrosis in patients with chronic myelogenous leukemia","volume":"101","author":"Bueso-Ramos","year":"2004","journal-title":"Cancer"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2634","DOI":"10.1038\/s41375-022-01682-2","article-title":"Splenic red pulp macrophages provide a niche for CML stem cells and induce therapy resistance","volume":"36","author":"Buhrer","year":"2022","journal-title":"Leukemia"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.3324\/haematol.2022.280922","article-title":"Targeting cytokine-induced leukemic stem cell persistence in chronic myeloid leukemia by IKK2-inhibition","volume":"108","author":"Butow","year":"2023","journal-title":"Haematologica"},{"key":"B16","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1002\/ajh.25342","article-title":"Treatment-free remission with first- and second-generation tyrosine kinase inhibitors","volume":"94","author":"Cortes","year":"2019","journal-title":"Am. J. Hematol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2172","DOI":"10.1038\/leu.2012.104","article-title":"Standardized definitions of molecular response in chronic myeloid leukemia","volume":"26","author":"Cross","year":"2012","journal-title":"Leukemia"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e4610","DOI":"10.21769\/BioProtoc.4610","article-title":"Updated: Semi-quantitative determination of protein expression using immunohistochemistry staining and analysis","volume":"2","author":"Crowe","year":"2023","journal-title":"Bio Protoc."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1172\/JCI19603","article-title":"Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis","volume":"114","author":"Daniels","year":"2004","journal-title":"J. Clin. Invest."},{"key":"B20","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1038\/ncb3530","article-title":"Leptin-receptor-expressing bone marrow stromal cells are myofibroblasts in primary myelofibrosis","volume":"19","author":"Decker","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1179\/1607845414Y.0000000221","article-title":"Bone marrow fibrosis may be an effective independent predictor of the 'TKI drug response level' in chronic myeloid leukemia","volume":"20","author":"Eliacik","year":"2015","journal-title":"Hematology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1016\/j.ajpath.2017.04.006","article-title":"Endothelial-to-Mesenchymal transition in bone marrow and spleen of primary myelofibrosis","volume":"187","author":"Erba","year":"2017","journal-title":"Am. J. Pathol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1097\/MOH.0000000000000669","article-title":"Still a burning question: The interplay between inflammation and fibrosis in myeloproliferative neoplasms","volume":"28","author":"Gleitz","year":"2021","journal-title":"Curr. Opin. Hematol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1182\/blood.v37.2.152.152","article-title":"Myelofibrosis in chronic granulocytic leukemia","volume":"37","author":"Gralnick","year":"1971","journal-title":"Blood"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.29271\/jcpsp.2019.11.1096","article-title":"Myelofibrosis in patients of chronic myeloid leukemia in chronic phase at presentation","volume":"29","author":"Hamid","year":"2019","journal-title":"J. Coll. Physicians Surg. Pak"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1182\/blood-2010-12-326843","article-title":"Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival","volume":"119","author":"Hamilton","year":"2012","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1080\/10428190801896103","article-title":"Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib","volume":"49","author":"Hantschel","year":"2008","journal-title":"Leuk. Lymphoma"},{"key":"B28","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1186\/s12885-019-5871-2","article-title":"Infliximab therapy together with tyrosine kinase inhibition targets leukemic stem cells in chronic myeloid leukemia","volume":"19","author":"Herrmann","year":"2019","journal-title":"BMC Cancer"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3758","DOI":"10.1182\/blood-2010-03-273979","article-title":"Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: An analysis from the international randomized study of interferon and STI571 (IRIS)","volume":"116","author":"Hughes","year":"2010","journal-title":"Blood"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.1038\/leu.2017.73","article-title":"Increased megakaryocytic proliferation, pro-platelet deposition and expression of fibrosis-associated factors in children with chronic myeloid leukaemia with bone marrow fibrosis","volume":"31","author":"Hussein","year":"2017","journal-title":"Leukemia"},{"key":"B31","doi-asserted-by":"publisher","first-page":"6443","DOI":"10.1016\/s0021-9258(18)48258-0","article-title":"Regulation of fibronectin and type I collagen mRNA levels by transforming growth factor-beta","volume":"262","author":"Ignotz","year":"1987","journal-title":"J. Biol. Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2701","DOI":"10.3892\/ol.2018.8890","article-title":"Ecotropic viral integration site 1 regulates the progression of acute myeloid leukemia via MS4A3-mediated TGF\u03b2\/EMT signaling pathway","volume":"16","author":"Jiang","year":"2018","journal-title":"Oncol. Lett."},{"key":"B33","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1080\/10428190500097581","article-title":"The degree of bone marrow fibrosis in chronic myelogenous leukemia is not a prognostic factor with imatinib mesylate therapy","volume":"46","author":"Kantarjian","year":"2005","journal-title":"Leuk. Lymphoma"},{"key":"B35","doi-asserted-by":"publisher","first-page":"2111","DOI":"10.1182\/blood-2018-02-834820","article-title":"The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis","volume":"131","author":"Kramann","year":"2018","journal-title":"Blood"},{"key":"B36","doi-asserted-by":"publisher","first-page":"2834","DOI":"10.1182\/blood-2013-07-517219","article-title":"Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts","volume":"124","author":"Krevvata","year":"2014","journal-title":"Blood"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1964","DOI":"10.1038\/s41375-019-0427-7","article-title":"Stem cell persistence in CML is mediated by extrinsically activated JAK1-STAT3 signaling","volume":"33","author":"Kuepper","year":"2019","journal-title":"Leukemia"},{"key":"B38","doi-asserted-by":"publisher","first-page":"2994","DOI":"10.1200\/JCO.2001.19.12.2994","article-title":"Bone marrow features improve prognostic efficiency in multivariate risk classification of chronic-phase ph(1+) chronic myelogenous leukemia: A multicenter trial","volume":"19","author":"Kvasnicka","year":"2001","journal-title":"J. Clin. Oncol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"3026","DOI":"10.1182\/blood-2008-06-158386","article-title":"Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence","volume":"112","author":"Lataillade","year":"2008","journal-title":"Blood"},{"key":"B40","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1111\/j.1365-2141.1986.tb04115.x","article-title":"Myelofibrosis in chronic granulocytic leukaemia: Clinicopathologic correlations and prognostic significance","volume":"64","author":"Lazzarino","year":"1986","journal-title":"Br. J. Haematol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1016\/j.stem.2020.11.004","article-title":"Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis","volume":"28","author":"Leimkuhler","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1016\/S1470-2045(10)70233-3","article-title":"Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: The prospective, multicentre stop imatinib (STIM) trial","volume":"11","author":"Mahon","year":"2010","journal-title":"Lancet Oncol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1002\/stem.1626","article-title":"Megakaryocytes contribute to the bone marrow-matrix environment by expressing fibronectin, type IV collagen, and laminin","volume":"32","author":"Malara","year":"2014","journal-title":"Stem Cells"},{"key":"B44","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1038\/s41467-019-14029-w","article-title":"A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration","volume":"11","author":"Matsushita","year":"2020","journal-title":"Nat. Commun."},{"key":"B45","doi-asserted-by":"publisher","first-page":"670580","DOI":"10.1155\/2015\/670580","article-title":"Circulating cytokine levels as markers of inflammation in Philadelphia negative myeloproliferative neoplasms: Diagnostic and prognostic interest","volume":"2015","author":"Mondet","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"B46","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nature08734","article-title":"TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia","volume":"463","author":"Naka","year":"2010","journal-title":"Nature"},{"key":"B47","doi-asserted-by":"publisher","first-page":"EC25","DOI":"10.7860\/JCDR\/2017\/25173.9650","article-title":"Morphological changes in bone marrow post imatinib therapy in chronic phase CML: A follow up study on sequential bone marrow aspirates and biopsies","volume":"11","author":"Narang","year":"2017","journal-title":"J. Clin. Diagn Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.immuni.2010.08.017","article-title":"The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche","volume":"33","author":"Omatsu","year":"2010","journal-title":"Immunity"},{"key":"B49","doi-asserted-by":"publisher","first-page":"100825","DOI":"10.1016\/j.blre.2021.100825","article-title":"Chronic Myeloid Leukemia: Modern therapies, current challenges and future directions","volume":"49","author":"Osman","year":"2021","journal-title":"Blood Rev."},{"key":"B50","first-page":"341","article-title":"Grading of marrow fibrosis in chronic myeloid leukemia-a comprehensive approach","volume":"48","author":"Rao","year":"2005","journal-title":"Indian J. Pathol. Microbiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/j.ccr.2011.10.012","article-title":"IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development","volume":"20","author":"Reynaud","year":"2011","journal-title":"Cancer Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1182\/blood-2013-02-483750","article-title":"Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: Results from the TWISTER study","volume":"122","author":"Ross","year":"2013","journal-title":"Blood"},{"key":"B52","first-page":"83","article-title":"WHO classification of tumours of haematopoietic and lymphoid tissues in 2008: An overview","volume":"102","author":"Sabattini","year":"2010","journal-title":"Pathologica"},{"key":"B53","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1111\/bjh.16506","article-title":"Prospects for achieving treatment-free remission in chronic myeloid leukaemia","volume":"190","author":"Saglio","year":"2020","journal-title":"Br. J. Haematol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3185","DOI":"10.1182\/blood-2009-04-215376","article-title":"BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells","volume":"115","author":"Schemionek","year":"2010","journal-title":"Blood"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1038\/leu.2011.366","article-title":"Leukemic spleen cells are more potent than bone marrow-derived cells in a transgenic mouse model of CML","volume":"26","author":"Schemionek","year":"2012","journal-title":"Leukemia"},{"key":"B55","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/j.stem.2013.06.009","article-title":"Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche","volume":"13","author":"Schepers","year":"2013","journal-title":"Cell Stem Cell"},{"key":"B56","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1016\/j.stem.2017.03.008","article-title":"Gli1(+) mesenchymal stromal cells are a key driver of bone marrow fibrosis and an important cellular therapeutic target","volume":"20","author":"Schneider","year":"2017","journal-title":"Cell Stem Cell"},{"key":"B57","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/s41467-017-02391-6","article-title":"Perturbation-response genes reveal signaling footprints in cancer gene expression","volume":"9","author":"Schubert","year":"2018","journal-title":"Nat. Commun."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1182\/blood-2016-08-734798","article-title":"Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment","volume":"129","author":"Shafat","year":"2017","journal-title":"Blood"},{"key":"B59","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1182\/bloodadvances.2018027516","article-title":"Bone marrow fibrosis associated with long-term imatinib therapy: Resolution after switching to a second-generation TKI","volume":"3","author":"Shanmuganathan","year":"2019","journal-title":"Blood Adv."},{"key":"B60","doi-asserted-by":"publisher","first-page":"7093","DOI":"10.3390\/ijms22137093","article-title":"Targeting leukemic stem cells in chronic myeloid leukemia: Is it worth the effort?","volume":"22","author":"Soverini","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B61","doi-asserted-by":"publisher","first-page":"1610","DOI":"10.1634\/stemcells.2006-0504","article-title":"Mesenchymal progenitors able to differentiate into osteogenic, chondrogenic, and\/or adipogenic cells in vitro are present in most primary fibroblast-like cell populations","volume":"25","author":"Sudo","year":"2007","journal-title":"Stem Cells"},{"key":"B62","volume-title":"WHO classification of Tumours of haematopoietic and lymphoid tissues","author":"Swerdlow","year":"2017"},{"key":"B63","doi-asserted-by":"publisher","first-page":"6175","DOI":"10.1182\/bloodadvances.2020003117","article-title":"Expansion of senescent megakaryocyte-lineage cells maintains CML cell leukemogenesis","volume":"4","author":"Tanabe","year":"2020","journal-title":"Blood Adv."},{"key":"B64","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1136\/jclinpath-2015-203320","article-title":"Imatinib reduces bone marrow fibrosis and overwhelms the adverse prognostic impact of reticulin formation in patients with chronic myeloid leukaemia","volume":"69","author":"Tanrikulu Simsek","year":"2016","journal-title":"J. Clin. Pathol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"95","DOI":"10.7326\/0003-4819-76-1-95","article-title":"Unfavorable signs in patients with chronic myelocytic leukemia","volume":"76","author":"Theologides","year":"1972","journal-title":"Ann. Intern Med."},{"key":"B66","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/sj.bmt.1702505","article-title":"Relevance and dynamics of myelofibrosis regarding hematopoietic reconstitution after allogeneic bone marrow transplantation in chronic myelogenous leukemia-a single center experience on 160 patients","volume":"26","author":"Thiele","year":"2000","journal-title":"Bone Marrow Transpl."},{"key":"B67","first-page":"1128","article-title":"European consensus on grading bone marrow fibrosis and assessment of cellularity","volume":"90","author":"Thiele","year":"2005","journal-title":"Haematologica"},{"key":"B68","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.14670\/HH-19.1277","article-title":"Effects of the tyrosine kinase inhibitor imatinib mesylate (STI571) on bone marrow features in patients with chronic myelogenous leukemia","volume":"19","author":"Thiele","year":"2004","journal-title":"Histol. Histopathol."},{"key":"B69","first-page":"430","article-title":"New insights into the pathogenesis of chronic myeloid leukaemia: Towards a path to cure","volume":"69","author":"Thielen","year":"2011","journal-title":"Neth J. Med."},{"key":"B70","unstructured":"Development and validation of a transcriptional signature for the assessment of fibrosis in organs\n            WangB.\n            ChenS.\n            GianH.\n            ChenR.\n            HeY.\n            ZhangX.\n          2020"},{"key":"B71","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.ccell.2015.04.004","article-title":"Treatment of chronic myelogenous leukemia by blocking cytokine alterations found in normal stem and progenitor cells","volume":"27","author":"Welner","year":"2015","journal-title":"Cancer Cell"},{"key":"B72","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/j.leukres.2012.02.011","article-title":"Imatinib mesylate discontinuation in patients with chronic myeloid leukemia who have received front-line imatinib mesylate therapy and achieved complete molecular response","volume":"36","author":"Yhim","year":"2012","journal-title":"Leuk. Res."},{"key":"B73","doi-asserted-by":"publisher","first-page":"2671","DOI":"10.1182\/blood-2015-11-679928","article-title":"Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor-treated CML stem cells","volume":"128","author":"Zhang","year":"2016","journal-title":"Blood"},{"key":"B74","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/j.ccr.2012.02.018","article-title":"Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia","volume":"21","author":"Zhang","year":"2012","journal-title":"Cancer Cell"},{"key":"B75","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.3324\/haematol.2018.205856","article-title":"Bone marrow adipose tissue-derived stem cell factor mediates metabolic regulation of hematopoiesis","volume":"104","author":"Zhang","year":"2019","journal-title":"Haematologica"},{"key":"B76","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1038\/nm.3706","article-title":"Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells","volume":"20","author":"Zhao","year":"2014","journal-title":"Nat. Med."},{"key":"B77","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1038\/ncb3570","article-title":"Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF","volume":"19","author":"Zhou","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"B78","doi-asserted-by":"publisher","first-page":"2592","DOI":"10.1089\/scd.2011.0572","article-title":"Fibroblastic potential of CD41+ cells in the mouse aorta-gonad-mesonephros region and yolk sac","volume":"21","author":"Zhou","year":"2012","journal-title":"Stem Cells Dev."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1212392\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T06:38:53Z","timestamp":1688452733000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1212392\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,4]]},"references-count":78,"alternative-id":["10.3389\/fphar.2023.1212392"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1212392","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,4]]},"article-number":"1212392"}}