The BCR/ABL oncogene alters the chemotactic response to stromal-derived factor-1alpha.
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.
Salgia
R
R
Department of Medical Oncology, Division of Hematologic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. ravi_salgia@dfci.harvard.edu
Quackenbush
E
E
Lin
J
J
Souchkova
N
N
Sattler
M
M
Ewaniuk
D S
DS
Klucher
K M
KM
Daley
G Q
GQ
Kraeft
S K
SK
Sackstein
R
R
Alyea
E P
EP
von Andrian
U H
UH
Chen
L B
LB
Gutierrez-Ramos
J C
JC
Pendergast
A M
AM
Griffin
J D
JD
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000473:pathology* / Q000502:physiology*; D006801:Humans; D051379:Mice
D019380:Anti-HIV Agents; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016044:Fusion Proteins, bcr-abl