Interaction of interleukin-7 and interleukin-3 with the CXCL12-induced proliferation of B-cell progenitor acute lymphoblastic leukemia.
OBJECTIVE
The chemokine stroma-derived factor 1a (SDF-1a or CXCL12) is essential for proliferation of B lineage acute lymphoblastic leukemia (ALL) cells in their physiological microenvironment, bone marrow stroma. CXCL12 synergizes with cytokines that stimulate myeloid cells, but its interaction with cytokines affecting lymphoid cells has not been examined. We investigated whether interleukin (IL)-7 and IL-3 interact with CXCL12 to regulate ALL proliferation.


METHODS
The survival of ALL cells in serum-free cultures, with or without stromal support and cytokines, was assessed by flow cytometry, and proliferation by 3H-thymidine incorporation. Signaling mechanisms were assessed by western blotting of phosphorylated forms of signaling molecules and by the use of specific inhibitors.


RESULTS
CXCL12, IL-3, and IL-7 had only marginal effects on ALL cell survival under serum-free conditions. However, these molecules individually induced significant proliferative responses in stromal cultures of 11 cases of ALL. The combination of CXCL12 with IL-7 or IL-3 produced a variety of responses, with clear synergistic or additive interactions observed in four cases. Synergistic proliferation in response to CXCL12 plus IL-7 was associated with enhanced phosphorylation of the mitogen-activated protein kinases, ERK-1/2 and p38, and AKT, and was partially inhibited by pretreatment of cells with inhibitors for p38 MAPK and phosphatidylinositol 3-kinase, implicating these pathways in the proliferation in response to IL-7 plus CXCL12.


CONCLUSIONS
These findings indicate a complex interaction between signaling from the CXCR4 receptor on ALL cells with those initiated by the cytokines IL-7 and IL-3, suggesting that CXCL12 may facilitate ALL proliferation by enhancing cytokine-signaling pathways in responsive cases.
Juarez
Julius
J
Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW, Australia.
Baraz
Rana
R
Gaundar
Shivashni
S
Bradstock
Kenneth
K
Bendall
Linda
L
D000293:Adolescent; D017209:Apoptosis; D001402:B-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D001773:Blood Cells / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D002867:Chromones / Q000494:pharmacology; D018920:Coculture Techniques; D016895:Culture Media, Serum-Free; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007223:Infant; D007377:Interleukin-3 / Q000494:pharmacology*; D015851:Interleukin-7 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D002867:Chromones; D016895:Culture Media, Serum-Free; D007093:Imidazoles; D007377:Interleukin-3; D015851:Interleukin-7; D009025:Morpholines; D009363:Neoplasm Proteins; D011725:Pyridines; D019718:Receptors, CXCR4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580