It is an important challenge to better understand the mechanisms of
tyrosine kinase inhibitors-induced apoptosis in CML cells. Thus, we have investigated how this apoptosis can be modulated by extracellular factors. Apoptosis induced by
imatinib and
nilotinib was determined in BCR-ABL expressing cell lines and primary CML CD34+ cells. Both molecules induced apoptosis of BCR-ABL expressing cells. This apoptosis was inhibited by
protein synthesis inhibition in both K562 and CML CD34+ cells. In K562, 80% inhibition of the BCR-ABL auto-phosphorylation by either
imatinib or
nilotinib induced a two fold increase in Bim-EL expression and induction of apoptosis in 48 h. Bim accumulation preceded apoptosis induction which was completely abolished by depletion in Bim using
shRNA. However, the anti-proliferative effect of
imatinib was preserved in Bim-depleted cells. When K562 cells were cultured in a
cytokine containing medium, the pro-apoptotic effect of
nilotinib was decreased by 68% and this was related to a decrease in Bim-EL dephosphorylation and accumulation. Similarly, the presence of a combination of
cytokines inhibited 88% of NIL- and 39% of IMA-induced apoptosis in primary CML CD34+ cells. In conclusion, both
nilotinib and
imatinib induce apoptosis through Bim accumulation independently of cell cycle arrest. However, the pro-apoptotic effect of both molecules can be attenuated by the presence of
cytokines and
growth factors, particularly concerning
nilotinib. Thus BCR-ABL inhibition restores the
cytokine dependence but is not sufficient to induce apoptosis when other signaling pathways are activated.