Résumé
The Bcr-Abl inhibitor imatinib is now the first line therapy for all newly diagnosed CML patients in chronic phase. Nevertheless resistance to the drug emerges as CML progresses to an acute deadly phase. Additional cellular targets should thus be identified to develop alternative therapeutic strategies. The transcription factor NF-kB is a pro-survival factor, found abnormally active in numerous hematologic malignancies. In the present study we show that the constitutive and abnormal activation of NF-kB in Bcr-Abl transformed BaF3 cells and in the LAMA84 CML line could be downregulated after inhibition of Bcr-Abl. Pharmacological blockade of NF-kB by the IKK2 inhibitor AS602868 (Serono International S.A.) prevented proliferation of BaF3/Bcr-Abl, LAMA84 and primary CML cells. Importantly, AS602868 led to apoptosis of an imatinib resistant variant of LAMA84 and of BaF3 clones expressing mutated form of Bcr-Abl derived from imatinib resistant patients. Moreover, NF-kB inhibition affected proliferation and hematopoietic colony formation of primary imatinib resistant CML cells. Finally, the IKK2 inhibitor prolonged survival of mice intravenously injected with the imatinib resistant clone LAMA84-r. Our data strongly suggest that NF-kB mediates important survival functions in CML cells for bcr-abl and that targeting NF-kB with the IKK2 inhibitor AS602868 may represent a new promising therapeutic strategy for CML treatment.