Document Detail


The BCR/ABL oncogene alters the chemotactic response to stromal-derived factor-1alpha.
MedLine Citation:
PMID:  10590068     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The chemokine stromal-derived factor-1alpha (SDF-1alpha) is a chemoattractant for CD34(+) progenitor cells, in vitro and in vivo. The receptor for SDF-1alpha, CXCR-4, is a 7 transmembrane domain receptor, which is also a coreceptor for human immunodeficiency virus (HIV). Here we show that transformation of hematopoietic cell lines by BCR/ABL significantly impairs their response to SDF-1alpha. Three different hematopoietic cell lines, Ba/F3, 32Dcl3, and Mo7e, were found to express CXCR-4 and to respond to SDF-1alpha with increased migration in a transwell assay. In contrast, after transformation by the BCR/ABL oncogene, the chemotactic response to SDF-1alpha was reduced in all 3 lines. This effect was directly due to BCR/ABL, because Ba/F3 cells, in which the expression of BCR/ABL could be regulated by a tetracycline-inducible promoter, also had reduced chemotaxis to SDF-1alpha when BCR/ABL was induced. The reduced response to SDF-1alpha was not due to an inability of BCR/ABL-transformed cell lines to migrate in general, as spontaneous motility of BCR/ABL-transformed cells was increased. In mice, injection of SDF-1alpha into the spleen resulted in a transient accumulation of untransformed Ba/F3 cells, but not Ba/F3. p210(BCR/ABL) cells administered simultaneously. The mechanism may involve inhibition of CXCR-4 receptor function, because in BCR/ABL-transformed cells, CXCR-4 receptors were expressed on the cell surface, but SDF-1alpha calcium flux was inhibited. Because SDF-1alpha and CXCR-4 are felt to be involved in progenitor cell homing to marrow, the abnormality decribed here could contribute to the homing and retention defects typical of immature myeloid cells in chronic myelogenous leukemia.
Authors:
R Salgia; E Quackenbush; J Lin; N Souchkova; M Sattler; D S Ewaniuk; K M Klucher; G Q Daley; S K Kraeft; R Sackstein; E P Alyea; U H von Andrian; L B Chen; J C Gutierrez-Ramos; A M Pendergast; J D Griffin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Blood     Volume:  94     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  1999 Dec 
Date Detail:
Created Date:  2000-01-10     Completed Date:  2000-01-10     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  4233-46     Citation Subset:  AIM; IM; X    
Affiliation:
Department of Medical Oncology, Division of Hematologic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. ravi_salgia@dfci.harvard.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-HIV Agents / pharmacology*
Cell Transformation, Neoplastic / genetics
Chemokine CXCL12
Chemokines, CXC / pharmacology*
Chemotaxis / drug effects,  genetics*
Fusion Proteins, bcr-abl / genetics*
Gene Expression Regulation, Neoplastic
Hematopoietic Stem Cells / pathology*,  physiology*
Humans
Mice
Grant Support
ID/Acronym/Agency:
CA 75348/CA/NCI NIH HHS; DK 560654/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Anti-HIV Agents; 0/CXCL12 protein, human; 0/Chemokine CXCL12; 0/Chemokines, CXC; 0/Cxcl12 protein, mouse; 0/Fusion Proteins, bcr-abl

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