p210BCR-ABL inhibits SDF-1 chemotactic response via alteration of CXCR4 signaling and down-regulation of CXCR4 expression.
It has been shown that p210(BCR-ABL) significantly impairs CXCR4 signaling. We report here that the migratory response to SDF-1 was profoundly altered in blast crisis, whereas chronic-phase CD34(+) cells migrated normally to this chemokine. This migratory defect was associated with a low CXCR4 membrane expression. In vitro STI-571 treatment of CD34(+) cells from patients in blast crisis markedly increased the CXCR4 transcript and CXCR4 membrane expression. Because p210(BCR-ABL) frequently increases with disease progression, we determined the effects of high and low p210(BCR-ABL) expression on CXCR4 protein in the granulocyte macrophage colony-stimulating factor-dependent human cell line MO7e. p210(BCR-ABL) expression distinctly alters CXCR4 protein through two different mechanisms depending on its expression level. At low expression, a signaling defect was detected with no modification of CXCR4 expression. However, higher p210(BCR-ABL) expression induced a marked down-regulation of CXCR4 that is related to its decreased transcription. The effect of p210(BCR-ABL) required its tyrosine kinase activity. Collectively, these data indicate that p210(BCR-ABL) could affect CXCR4 by more than one mechanism and suggest that down-regulation of CXCR4 may have important implications in chronic myelogenous leukemia pathogenesis.
Geay
Jean-Francois
JF
Institut National de la Sante et de la Recherche Medicale, Institut Gustave Roussy, Villejuif, France.
Buet
Dorothée
D
Zhang
Yanyan
Y
Foudi
Adlen
A
Jarrier
Peggy
P
Berthebaud
Magali
M
Turhan
Ali G
AG
Vainchenker
William
W
Louache
Fawzia
F
D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D001549:Benzamides; D001752:Blast Crisis; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors* / Q000502:physiology; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D041681:NIH 3T3 Cells; D010879:Piperazines / Q000494:pharmacology; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic
D018952:Antigens, CD34; D001549:Benzamides; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D010879:Piperazines; D011743:Pyrimidines; D019718:Receptors, CXCR4; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl