Childhood Acute lymphoblastic leukemia (ALL) has experienced a dramatic improvement in survival rates over the past 40 years. At this time, the likelihood of cure is greater than 70%. Despite such success, relapse still occurs in 25–30% of children. The major cause of treatment failure is intrinsic or acquired drug resistance. It has been reported that stromal cells of the bone marrow (BMSC) provide a sanctuary in which subpopulations of leukaemia cells can evade chemotherapy-induced death and acquire a drug-resistant phenotype. This explains why, when ALL cell lines are cultured on human BMSC, the apoptotic effect of chemotherapic drugs is strongly inhibited. The mechanisms of BMSC-mediated protection involve a complex interplay among stroma-derived factors, in particular the SDF-1a and the chemokine receptor CXCR4. For these reasons, CXCR4-targeting compounds are nowadays considered potential therapeutic tools in ALL (

Burger JA and Burkle A, Br J Haematol 137: 288–296, 2007
). An additive mechanism of BMSC-induced protection involeves the interaction between adhesion receptors on leukaemia cells and adhesion molecules, like fibronectin, on the surface of BMSC (
Tabe Y et al, Cancer Res 67:1238–1250, 2007
). Recent evidence indicates that integrins trigger survival signals since they form macromolecular complexes with plasma membrane proteins. A novel integrin partner in such complexes is represented by ion channel proteins. The channel protein is not merely a bystander interactor, but it often feeds back by controlling integrin activation and downstream signaling (
Arcangeli A et al, Trends Cell Biol 16:631–639, 2006
). This mechanisms can give a molecular explanation to the recent evidences that ion channels, especially K+ channels, mark and regulate specific stages of cancer progression, and hence may represent novel targets for cancer therapy. (
Becchetti A. and Arcangeli A., J. Gen. Physiol., 28: 313–314, 2008
). Among ion channels, hERG1 channels, are capable of forming multiprotein complexes with integrins in tumor cells. We report here the discovery of a peculiar multiprotein complex formed by CXCR4 and the b1 integrin subunit, besides hERG1 channels, occurring in B-ALL cells. The assembly of the complex is stimulated by adhesion onto BMSC, and is further modulated by SDF-1a. Furthermore, the hERG1/beta1/CXCR4 complex triggers the activation of different intracellular signalling pathways (MAPK activation, pAKT phosphorylation). All the BMSC-induced signalling pathways are strongly inhibited by hERG1 channel blockers. Finally, when cultured on BMSC, all the B-ALL cell lines experienced a strong reduction of apoptosis after treatment with chemotherapic drugs (doxorubicin, prednisone, L-asparaginase, metothrexate). The addition of specific hERG1 blockers bypasses drug resistance, promptly restoring a significant apoptosis in leukemia cells. On the whole, our results allow to include hERG1 channels in a scheme where they act as upstream regulators of integrin/chemokine receptors pro survival signals. In addition data here presented indicate a potential role for hERG1 inhibitors as a novel strategy for overcoming drug resistance in the treatment of ALL.

Topics:
burkitt's lymphoma, chemotherapy regimen, child, cxcr4 receptors, leukemia, signal transduction, integrins, ion channels, adhesions, chemokine receptors

Disclosures: No relevant conflicts of interest to declare.

This work was supported by “Associazione Noi per Voi”, Firenze and Associazione Italiana per la Ricerca sul Cancro (AIRC).

Author notes

Corresponding author

2008, The American Society of Hematology
2008
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