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J Exp Med. 2013 Nov 18;210(12):2661-73. doi: 10.1084/jem.20130112. Epub 2013 Oct 28.

MIP-1α/CCL3-mediated maintenance of leukemia-initiating cells in the initiation process of chronic myeloid leukemia.

Author information

1
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.

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.

PMID:
24166712
PMCID:
PMC3832924
DOI:
10.1084/jem.20130112
[Indexed for MEDLINE]
Free PMC Article

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