Published online 5 March 2008
Haematologica, Vol 93, Issue 4, 524-532 doi:10.3324/haematol.12098
Copyright © 2008 by Ferrata Storti Foundation
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Acute Lymphoblastic Leukemia

Bone marrow stromal cells and the upregulation of interleukin-8 production in human T-cell acute lymphoblastic leukemia through the CXCL12/CXCR4 axis and the NF-{kappa}B and JNK/AP-1 pathways

Maria T. Scupoli1,2, Massimo Donadelli3, Federica Cioffi2, Maria Rossi2, Omar Perbellini2, Giorgio Malpeli4, Silvia Corbioli2, Fabrizio Vinante2, Mauro Krampera2, Marta Palmieri3, Aldo Scarpa4, Cristina Ariola5, Robin Foà5, Giovanni Pizzolo2

1 Interdepartmental Laboratory for Medical Research (LURM)
2 Department of Clinical and Experimental Medicine -Section of Hematology
3 Department of Morphological-Biomedical Sciences, Section of Biological Chemistry
4 Department of Pathology, Section of Pathological Anatomy, University of Verona;
5 Department of Cellular Biotechnologies and Hematology, University ‘La Sapienza’, Rome, Italy

Correspondence: Maria Teresa Scupoli, PhD, Laboratorio Universitario di Ricerca, Medica (LURM), Policlinico, G.B. Rossi, piazzale L. Scuro 10, 37134 Verona, Italy., E-mail:mariateresa.scupoli{at}univr.it

Background: Cytokines released in the bone marrow and thymic microenvironments play a key role in the growth of T-cell acute lymphoblastic leukemia. Among such cytokines, interleukin-8 is highly expressed in T-cell acute lymphoblastic leukemia cells refractory to chemotherapy. In this study we explored whether bone marrow stromal cells can regulate IL-8 expression in T-cell acute lymphoblastic leukemia and investigated the role of the stromal CXCL12 chemokine in this event. We also investigated the roles of the nuclear factor-{kappa}B and Jun-N-terminal kinase (JNK)/activating protein (AP)-1 signaling pathways, which contribute to regulate interleukin-8 production in some cells.

Design and Methods: We analyzed the expression of interleukin-8 in primary cells from ten adult patients with T-cell acute lymphoblastic leukemia when these cells were cultured with bone marrow stromal cells or stimulated with exogenous CXCL12. Interleukin-8 mRNA was analyzed by a colorimetric assay. Cytokine production was assayed by cytometric antibody array and flow cytometry. Nuclear factor-{kappa}B and JNK/AP-1 activation was investigated by using specific inhibitors of these pathways, immunoblotting, electrophoretic mobility-shift assay and cell transfection assays.

Results: Bone marrow stromal cells upregulated interleukin-8 mRNA in T-cell acute lymphoblastic leukemia cells through the activity of CXCR4, the CXCL12 receptor, as assessed by the use of neutralizing antibodies. Exogenous CXCL12 induced a significant increase in the production of IL-8 mRNA and protein in all T-cell acute lymphoblastic leukemia cases. We showed that CXCL12 activates the nuclear factor-{kappa}B and JNK/AP-1 pathways, and that these events are required for increased expression of interleukin-8. Furthermore, the nuclear factor-{kappa}B and AP-1 elements of the interleukin-8 promoter are necessary for both constitutive and CXCL12-induced interleukin-8 expression.

Conclusions: Interleukin-8 is physiologically regulated by the CXCL12/CXCR4 axis and the nuclear factor-{kappa}B and JNK/AP-1 pathways are required for interleukin-8 expression in T-cell acute lymphoblastic leukemia. We propose that, by upregulating interleukin-8, the bone marrow microenvironment and the CXCL12/CXCR4 axis may play a role in the pathogenesis of T-cell acute lymphoblastic leukemia.

Key words: acute lymphoid leukemias, chemokines, tumor microenvironment.


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Signaling pathways involved in the development of T-cell acute lymphoblastic leukemia
Frank J.T. Staal, Anton W. Langerak
Haematologica 2008 93: 493-497. [Full Text] [PDF]



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F. J.T. Staal and A. W. Langerak
Signaling pathways involved in the development of T-cell acute lymphoblastic leukemia
Haematologica, April 1, 2008; 93(4): 493 - 497.
[Full Text] [PDF]