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-kappaB and JNK/AP-1 pathways

Haematologica. 2008 Apr;93(4):524-32. doi: 10.3324/haematol.12098. Epub 2008 Mar 5.


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-kappaB 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-kappaB 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-kappaB and JNK/AP-1 pathways, and that these events are required for increased expression of interleukin-8. Furthermore, the nuclear factor-kappaB 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-kappaB 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bone Marrow Cells / metabolism*
  • Chemokine CXCL12 / pharmacology
  • Chemokine CXCL12 / physiology*
  • Clinical Trials as Topic / statistics & numerical data
  • Gene Expression Regulation, Leukemic / drug effects
  • Gene Expression Regulation, Leukemic / physiology*
  • Humans
  • Interleukin-8 / biosynthesis*
  • Interleukin-8 / genetics
  • Interleukin-8 / physiology
  • JNK Mitogen-Activated Protein Kinases / physiology*
  • Jurkat Cells / drug effects
  • Jurkat Cells / metabolism
  • Leukemia-Lymphoma, Adult T-Cell / genetics
  • Leukemia-Lymphoma, Adult T-Cell / metabolism*
  • Multicenter Studies as Topic / statistics & numerical data
  • NF-kappa B / physiology*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • RNA, Messenger / biosynthesis
  • RNA, Neoplasm / biosynthesis
  • Receptors, CXCR4 / physiology*
  • Recombinant Fusion Proteins / physiology
  • Stromal Cells / metabolism*
  • Transcription Factor AP-1 / physiology*
  • Transfection
  • Up-Regulation / drug effects
  • Up-Regulation / physiology*


  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Interleukin-8
  • NF-kappa B
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • Receptors, CXCR4
  • Recombinant Fusion Proteins
  • Transcription Factor AP-1
  • JNK Mitogen-Activated Protein Kinases