Unique SDF-1-induced activation of human precursor-B ALL cells as a result of altered CXCR4 expression and signaling.
The mechanisms governing migration and extramedullary dissemination of leukemic cells remain obscure. In this study the migration and in vivo homing to the bone marrow of nonobese diabetic severe combined immunodeficient (NOD/SCID) mice injected with human precursor-B acute lymphoblastic leukemia (ALL) cells in comparison to normal CD34+ progenitors (both cord blood and mobilized peripheral blood) was investigated. Although migration and homing of both cell populations was dependent on stromal cell-derived factor 1 (SDF-1)/CXCR4 interactions, major differences in receptor expression as well as the migratory capacity toward various concentrations of SDF-1 were found. Furthermore, unlike normal CD34+ progenitors, in vivo homing of the leukemic cells was superior when recipient NOD/SCID mice were not irradiated prior to transplantation. In addition, we report differences in the adhesion molecules activated following SDF-1 stimulation, documenting a major role for very late antigen 4 (VLA-4), but not VLA-5 and lymphocyte function-associated antigen-1 (LFA-1), in homing of precursor-B ALL cells. Interestingly, Toxin-B and pertussis toxin inhibited the homing of the leukemic cells but not that of normal CD34+ progenitors or normal CD10+/CD19+ precursor-B cells, revealing differences in CXCR4 signaling pathways that are based on changes that acquired by the leukemic cells. Altogether, our data provide new insights into different SDF-1-induced signaling, activation, and consequent motility between normal CD34+ and precursor-B ALL progenitors, which may lead to improved clinical protocols.
Spiegel
Asaf
A
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Kollet
Orit
O
Peled
Amnon
A
Abel
Loya
L
Nagler
Arnon
A
Bielorai
Bella
B
Rechavi
Gideon
G
Vormoor
Josef
J
Lapidot
Tsvee
T
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D002051:Burkitt Lymphoma / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D005312:Fetal Blood / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D019718:Receptors, CXCR4 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D020782:Matrix Metalloproteinases