Differential effect of interferon alpha on chronic myelogenous leukaemia and normal haematopoietic progenitors in a stromal cell co-culture context: role of the flt3 ligand.
Interferon alpha (IFN-alpha) is used to treat chronic myelogenous leukaemia (CML) patients. However, its target(s) remain(s) unknown. One possibility is that there is a differing sensitivity of the leukaemic from the normal colony-forming cell (CFC) compartments to IFN-alpha. Co-cultures of progenitors with stromal cells provide a valuable tool to dissect direct and indirect activities of IFN-alpha. In this study, we have used endothelial cells (EC) as a source of stromal cells. In co-cultures of normal progenitors with EC, IFN-alpha increased the generation of clonogenic cells, mainly via an increased production of flt3 ligand (FL) by EC. In contrast, in co-cultures of CML progenitors with EC, IFN-alpha inhibited the generation of clonogenic cells, mainly by direct inhibition on the progenitors, the up-regulation of FL production by stromal cells being unable to compensate for the direct inhibitory effects of IFN-alpha. These data provide evidence for a differential effect of IFN-alpha on the growth of CML and normal CFC cells in a stromal context and suggest that an alteration in the response of CML progenitor cells to FL is important in the explanation of this differential effect.
Solanilla
A
A
FR 60, Biologie des Greffes, Université de Bordeaux 2, France. anne.solanilla@umr5540.u-bordeaux2.fr
El Andaloussi
A
A
Grosset
C
C
Duchez
P
P
Mossalayi
M D
MD
Mahon
F X
FX
Reiffers
J
J
Marit
G
G
Ripoche
J
J
D018952:Antigens, CD34 / Q000276:immunology; D002448:Cell Adhesion; D018929:Cell Culture Techniques / Q000379:methods; D002999:Clone Cells / Q000187:drug effects; D018920:Coculture Techniques; D004727:Endothelium / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*
D018952:Antigens, CD34; D016898:Interferon-alpha; D008565:Membrane Proteins; C084881:flt3 ligand protein