{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T18:48:51Z","timestamp":1790275731344,"version":"4.1.0"},"reference-count":43,"publisher":"Rockefeller University Press","issue":"12","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,11,18]]},"abstract":"<jats:p>In the initiation process of chronic myeloid leukemia (CML), a small number of transformed leukemia-initiating cells (LICs) coexist with a large number of normal hematopoietic cells, gradually increasing thereafter and eventually predominating in the hematopoietic space. However, the interaction between LICs and normal hematopoietic cells at the early phase has not been clearly delineated because of the lack of a suitable experimental model. In this study, we succeeded in causing a marked leukocytosis resembling CML from restricted foci of LICs in the normal hematopoietic system by direct transplantation of BCR-ABL gene\u2013transduced LICs into the bone marrow (BM) cavity of nonirradiated mice. Herein, we observed that BCR-ABL+lineage\u2212c-kit\u2212 immature leukemia cells produced high levels of an inflammatory chemokine, MIP-1\u03b1\/CCL3, which promoted the development of CML. Conversely, ablation of the CCL3 gene in LICs dramatically inhibited the development of CML and concomitantly reduced recurrence after the cessation of a short-term tyrosine kinase inhibitor treatment. Finally, normal hematopoietic stem\/progenitor cells can directly impede the maintenance of LICs in BM in the absence of CCL3 signal.<\/jats:p>","DOI":"10.1084\/jem.20130112","type":"journal-article","created":{"date-parts":[[2013,10,29]],"date-time":"2013-10-29T03:20:09Z","timestamp":1383016809000},"page":"2661-2673","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":52,"title":["MIP-1\u03b1\/CCL3-mediated maintenance of leukemia-initiating cells in the initiation process of chronic myeloid leukemia"],"prefix":"10.1084","volume":"210","author":[{"given":"Tomohisa","family":"Baba","sequence":"first","affiliation":[{"name":"Division of Molecular Bioregulation 1 , 2 , and 3"},{"name":"Exploratory Project on Cancer Stem Cells 1 , 2 , and 3"},{"name":"Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhito","family":"Naka","sequence":"additional","affiliation":[{"name":"Division of Molecular Bioregulation 1 , 2 , and 3"},{"name":"Exploratory Project on Cancer Stem Cells 1 , 2 , and 3"},{"name":"Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soji","family":"Morishita","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine and Stem Cell Regulation 4 and 5"},{"name":"Department of Hematology, Juntendo University School of Medicine, Tokyo 113-8421, Japan 4 and 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Komatsu","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine and Stem Cell Regulation 4 and 5"},{"name":"Department of Hematology, Juntendo University School of Medicine, Tokyo 113-8421, Japan 4 and 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Hirao","sequence":"additional","affiliation":[{"name":"Division of Molecular Bioregulation 1 , 2 , and 3"},{"name":"Exploratory Project on Cancer Stem Cells 1 , 2 , and 3"},{"name":"Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naofumi","family":"Mukaida","sequence":"additional","affiliation":[{"name":"Division of Molecular Bioregulation 1 , 2 , and 3"},{"name":"Exploratory Project on Cancer Stem Cells 1 , 2 , and 3"},{"name":"Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2013,10,28]]},"reference":[{"key":"2023072601280631200_bib1","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1084\/jem.185.1.111","article-title":"The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood","volume":"185","author":"Aiuti","year":"1997","journal-title":"J. Exp. Med."},{"key":"2023072601280631200_bib2","doi-asserted-by":"publisher","first-page":"7478","DOI":"10.4049\/jimmunol.0900542","article-title":"CCR5 ligands modulate CXCL12-induced chemotaxis, adhesion, and Akt phosphorylation of human cord blood CD34+ cells","volume":"183","author":"Basu","year":"2009","journal-title":"J. Immunol."},{"key":"2023072601280631200_bib3","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1172\/JCI118141","article-title":"Treatment of marrow stroma with interferon-alpha restores normal beta 1 integrin-dependent adhesion of chronic myelogenous leukemia hematopoietic progenitors. Role of MIP-1 alpha","volume":"96","author":"Bhatia","year":"1995","journal-title":"J. Clin. Invest."},{"key":"2023072601280631200_bib4","doi-asserted-by":"crossref","first-page":"3448","DOI":"10.4049\/jimmunol.150.8.3448","article-title":"Comparative analysis of the human macrophage inflammatory protein family of cytokines (chemokines) on proliferation of human myeloid progenitor cells. Interacting effects involving suppression, synergistic suppression, and blocking of suppression","volume":"150","author":"Broxmeyer","year":"1993","journal-title":"J. Immunol."},{"key":"2023072601280631200_bib5","doi-asserted-by":"publisher","first-page":"1987","DOI":"10.1084\/jem.189.12.1987","article-title":"Dominant myelopoietic effector functions mediated by chemokine receptor CCR1","volume":"189","author":"Broxmeyer","year":"1999","journal-title":"J. Exp. Med."},{"key":"2023072601280631200_bib6","doi-asserted-by":"crossref","first-page":"4270","DOI":"10.1182\/blood.V86.11.4270.bloodjournal86114270","article-title":"Macrophage inflammatory protein-1 alpha receptors are present on cells enriched for CD34 expression from patients with chronic myeloid leukemia","volume":"86","author":"Chasty","year":"1995","journal-title":"Blood."},{"key":"2023072601280631200_bib7","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1172\/JCI35721","article-title":"Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity","volume":"121","author":"Corbin","year":"2011","journal-title":"J. Clin. Invest."},{"key":"2023072601280631200_bib8","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1016\/j.ccr.2008.08.003","article-title":"Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation","volume":"14","author":"Dierks","year":"2008","journal-title":"Cancer Cell."},{"key":"2023072601280631200_bib9","doi-asserted-by":"publisher","first-page":"2408","DOI":"10.1056\/NEJMoa062867","article-title":"Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia","volume":"355","author":"Druker","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"2023072601280631200_bib10","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1182\/blood.V79.9.2221.2221","article-title":"Demonstration of stem cell inhibition and myeloprotective effects of SCI\/rhMIP1 alpha in vivo","volume":"79","author":"Dunlop","year":"1992","journal-title":"Blood."},{"key":"2023072601280631200_bib11","doi-asserted-by":"publisher","first-page":"12015","DOI":"10.1073\/pnas.90.24.12015","article-title":"Unresponsiveness of primitive chronic myeloid leukemia cells to macrophage inflammatory protein 1 alpha, an inhibitor of primitive normal hematopoietic cells","volume":"90","author":"Eaves","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072601280631200_bib12","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1038\/344442a0","article-title":"Identification and characterization of an inhibitor of haemopoietic stem cell proliferation","volume":"344","author":"Graham","year":"1990","journal-title":"Nature."},{"key":"2023072601280631200_bib13","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1038\/ncb1853","article-title":"Characterization of the interface between normal and transformed epithelial cells","volume":"11","author":"Hogan","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"2023072601280631200_bib14","doi-asserted-by":"publisher","first-page":"2260","DOI":"10.1056\/NEJMoa1002315","article-title":"Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia","volume":"362","author":"Kantarjian","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"2023072601280631200_bib15","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1182\/blood-2003-12-4369","article-title":"Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis","volume":"105","author":"Koschmieder","year":"2005","journal-title":"Blood."},{"key":"2023072601280631200_bib16","doi-asserted-by":"publisher","first-page":"1659","DOI":"10.1002\/cncr.20922","article-title":"Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up","volume":"103","author":"Lahaye","year":"2005","journal-title":"Cancer."},{"key":"2023072601280631200_bib17","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1084\/jem.189.9.1399","article-title":"The P190, P210, and P230 forms of the BCR\/ABL oncogene induce a similar chronic myeloid leukemia\u2013like syndrome in mice but have different lymphoid leukemogenic activity","volume":"189","author":"Li","year":"1999","journal-title":"J. Exp. Med."},{"key":"2023072601280631200_bib18","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/1756-9966-30-8","article-title":"Activation of the Hedgehog pathway in chronic myelogeneous leukemia patients","volume":"30","author":"Long","year":"2011","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"2023072601280631200_bib19","doi-asserted-by":"crossref","first-page":"3412","DOI":"10.1182\/blood.V85.12.3412.bloodjournal85123412","article-title":"Mobilization of early hematopoietic progenitor cells with BB-10010: a genetically engineered variant of human macrophage inflammatory protein-1 alpha","volume":"85","author":"Lord","year":"1995","journal-title":"Blood."},{"key":"2023072601280631200_bib20","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1016\/S0002-9440(10)63921-1","article-title":"Potential interaction between CCR1 and its ligand, CCL3, induced by endogenously produced interleukin-1 in human hepatomas","volume":"162","author":"Lu","year":"2003","journal-title":"Am. J. Pathol."},{"key":"2023072601280631200_bib21","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.4049\/jimmunol.149.3.1004","article-title":"Myelosuppressive effects in vivo of purified recombinant murine macrophage inflammatory protein-1 alpha","volume":"149","author":"Maze","year":"1992","journal-title":"J. Immunol."},{"key":"2023072601280631200_bib22","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1038\/nrc2147","article-title":"Chronic myeloid leukaemia as a model of disease evolution in human cancer","volume":"7","author":"Melo","year":"2007","journal-title":"Nat. Rev. Cancer."},{"key":"2023072601280631200_bib23","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1038\/nature03669","article-title":"Dynamics of chronic myeloid leukaemia","volume":"435","author":"Michor","year":"2005","journal-title":"Nature."},{"key":"2023072601280631200_bib24","doi-asserted-by":"publisher","first-page":"1528","DOI":"10.1182\/blood-2008-09-179697","article-title":"Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression","volume":"114","author":"Mumprecht","year":"2009","journal-title":"Blood."},{"key":"2023072601280631200_bib25","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.bcp.2010.04.003","article-title":"The bone marrow microenvironment as a sanctuary for minimal residual disease in CML","volume":"80","author":"Nair","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"2023072601280631200_bib26","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":"2023072601280631200_bib27","doi-asserted-by":"crossref","first-page":"3780","DOI":"10.1182\/blood.V92.10.3780","article-title":"Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr\/abl-transduced bone marrow","volume":"92","author":"Pear","year":"1998","journal-title":"Blood."},{"key":"2023072601280631200_bib28","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1038\/sj.leu.2405021","article-title":"Chemokine-mobilized adult stem cells; defining a better hematopoietic graft","volume":"22","author":"Pelus","year":"2008","journal-title":"Leukemia."},{"key":"2023072601280631200_bib29","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/S0092-8674(00)80679-0","article-title":"Ras1 promotes cellular growth in the Drosophila wing","volume":"100","author":"Prober","year":"2000","journal-title":"Cell."},{"key":"2023072601280631200_bib30","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1038\/nrc1567","article-title":"Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia","volume":"5","author":"Ren","year":"2005","journal-title":"Nat. Rev. Cancer."},{"key":"2023072601280631200_bib31","doi-asserted-by":"publisher","first-page":"2251","DOI":"10.1056\/NEJMoa0912614","article-title":"Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia","volume":"362","author":"Saglio","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"2023072601280631200_bib32","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1056\/NEJM199904293401706","article-title":"Chronic myeloid leukemia","volume":"340","author":"Sawyers","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"2023072601280631200_bib33","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.1016\/j.cellsig.2012.05.015","article-title":"Signaling pathways in chronic myeloid leukemia and leukemic stem cell maintenance: key role of stromal microenvironment","volume":"24","author":"Seke Etet","year":"2012","journal-title":"Cell. Signal."},{"key":"2023072601280631200_bib34","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/j.cyto.2012.03.011","article-title":"Role of radiation-induced granulocyte colony-stimulating factor in recovery from whole body gamma-irradiation","volume":"58","author":"Singh","year":"2012","journal-title":"Cytokine."},{"key":"2023072601280631200_bib35","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1038\/sj.gt.3300951","article-title":"Immune response to green fluorescent protein: implications for gene therapy","volume":"6","author":"Stripecke","year":"1999","journal-title":"Gene Ther."},{"key":"2023072601280631200_bib36","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1182\/blood-2011-02-339267","article-title":"Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells","volume":"118","author":"Tang","year":"2011","journal-title":"Blood."},{"key":"2023072601280631200_bib37","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1038\/sj.onc.1201914","article-title":"Abl protein kinase abrogates the response of multipotent haemopoietic cells to the growth inhibitor macrophage inflammatory protein-1 alpha","volume":"16","author":"Wark","year":"1998","journal-title":"Oncogene."},{"key":"2023072601280631200_bib38","doi-asserted-by":"publisher","first-page":"4122","DOI":"10.1182\/blood.V99.11.4122","article-title":"BCR-ABL-induced adhesion defects are tyrosine kinase-independent","volume":"99","author":"Wertheim","year":"2002","journal-title":"Blood."},{"key":"2023072601280631200_bib39","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":"2023072601280631200_bib40","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1038\/nature02041","article-title":"Identification of the haematopoietic stem cell niche and control of the niche size","volume":"425","author":"Zhang","year":"2003","journal-title":"Nature."},{"key":"2023072601280631200_bib41","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1093\/jnci\/djh024","article-title":"Mobilization of dendritic cell precursors into the circulation by administration of MIP-1alpha in mice","volume":"96","author":"Zhang","year":"2004","journal-title":"J. Natl. Cancer Inst."},{"key":"2023072601280631200_bib42","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1038\/nature07737","article-title":"Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia","volume":"458","author":"Zhao","year":"2009","journal-title":"Nature."},{"key":"2023072601280631200_bib43","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/31269","article-title":"Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development","volume":"393","author":"Zou","year":"1998","journal-title":"Nature."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/210\/12\/2661\/1746477\/jem_20130112.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/210\/12\/2661\/1746477\/jem_20130112.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T01:28:35Z","timestamp":1690334915000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/210\/12\/2661\/53773\/MIP-1-CCL3-mediated-maintenance-of-leukemia"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,10,28]]},"references-count":43,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2013,11,18]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20130112","relation":{},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2013,10,28]]}}}