title: MIP-1α/CCL3-mediated maintenance of leukemia-initiating cells in the initiation process of chronic myeloid leukemia.
abstract: 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-transduced LICs into the bone marrow (BM) cavity of nonirradiated mice. Herein, we observed that BCR-ABL(+)lineage(-)c-kit(-) immature leukemia cells produced high levels of an inflammatory chemokine, MIP-1α/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.
authors.affiliation: Division of Molecular Bioregulation, 2 Exploratory Project on Cancer Stem Cells, and 3 Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Baba
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Naka
authors.forename: Soji
authors.initials: S
authors.lastname: Morishita
authors.forename: Norio
authors.initials: N
authors.lastname: Komatsu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D054405:Chemokine CCL3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D016313:Genes, abl; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D054389:Receptors, CCR1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C496534:Ccl3 protein, mouse; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit