Growth advantage of chronic myeloid leukemia CFU-GM in vitro: survival to growth factor deprivation, possibly related to autocrine stimulation, is a more common feature than hypersensitivity to GM-CSF/IL3 and is efficiently counteracted by retinoids +- alpha-interferon.
Bcr/abl fusion gene, in experimental models, induces survival to growth factor deprivation and hypersensitivity to IL3. However, conflicting data were reported about chronic myeloid leukemia (CML) progenitors. We investigated the responsiveness of purified CML CFU-GM to GM-CSF/IL3 and their survival to growth factor deprivation. CFU-GM hypersensitivity to IL3 and/or GM-CSF was found in 3/11 CML cases only. CML CFU-GM survived well in stroma-free 'mass' culture (5 x 10(4) cells/ml) without cytokine addition, up to day 11, average recovery being around 95% in medium + 10% fetal bovine serum and 67-81% in serum-free medium. Conversely, normal progenitors declined steadily, particularly after extensive purification (18 +/- 10% recovery at the 7th day), and in serum-free medium (4 +/- 6% recovery). By contrast, normal and CML CFU-GM declined in a similar way in limiting dilution cultures (1-10 cells/50 microl). We also investigated the effects of retinoic acid and alpha-interferon on CFU-GM survival. Both all-trans- and 13-cis retinoic acid, particularly in combination with alpha-interferon, reduced CML CFU-GM recovery down to normal progenitors' values. In conclusion, hypersensitivity to CSFs is rare in CML, whereas resistance to growth factor deprivation has been confirmed in mass, but not in limiting, dilution cultures. Both stereoisomers of retinoic acid, at therapeutic concentrations and in combination with alpha-interferon, can overcome the survival advantage of CML progenitors.
Divisione di Ematologia dell'Università di Torino, Azienda Ospedaliera S Giovanni Battista, Italy.
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Foli
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Argentino
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Pileri
D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology*; D007938:Leukemia / Q000473:pathology*; D012176:Retinoids / Q000494:pharmacology*
D016898:Interferon-alpha; D007377:Interleukin-3; D012176:Retinoids; D016178:Granulocyte-Macrophage Colony-Stimulating Factor