Ia. Mayer et al., The p38 MAPK pathway mediates the growth inhibitory effects of interferon-alpha in BCR-ABL-expressing cells, J BIOL CHEM, 276(30), 2001, pp. 28570-28577
The mechanisms by which interferon-alpha (IFN-alpha) mediates its anti-leuk
emic effects in chronic myelogenous leukemia (CML) cells are not known. We
determined whether p38 MAPK is activated by IFN-alpha in BCR-ABLexpressing
cells and whether its function is required for the generation of growth inh
ibitory responses. IFN-alpha treatment induced phosphorylation/activation o
f p38 in the IFN-alpha -sensitive KT-1 cell line, but not in IFN-alpha -res
istant K562 cells. Consistent with this, IFN-alpha treatment of KT-1 (but n
ot K562) cells induced activation of the small GTPase Racl, which functions
as an upstream regulator of p38. In addition, IFN-alpha -dependent phospho
rylationfactivation of p38 was induced by treatment of primary granulocytes
isolated from the peripheral blood of patients with CAIL. To define the fu
nctional role of the Rac1/p38 ALkPK pathway in IFN-alpha signaling, the eff
ects of pharmacological inhibition of p38 on the induction of IFN-alpha res
ponses were determined. Treatment of KT-1 cells with the p38-specific inhib
itors SB203580 and SB202190 reversed the growth inhibitory effects of IFN-a
lpha. On the other hand, the MEK kinase inhibitor PD09SO59 had no effects,
further demonstrating the specificity of these findings. To directly determ
ine the significance of IFN-alpha -dependent activation of p38 in the induc
tion of the anti-leukemic effects of IFN-alpha, we evaluated the effects of
p38 inhibition on leukemic colony formation in bone marrow samples of pati
ents with CML. IFN-alpha inhibited leukemic granulocyte/ macrophage colony
formation in a dose-dependent manner, whereas concomitant treatment with p3
8 inhibitors reversed such an inhibition. Thus, the Rac1-/p38 MAPK pathway
is activated by IFN-alpha in BCR-ABL-expressing cells and appears to play a
key role in the generation of the growth inhibitory effects of IFN-alpha i
n CAIL cells.