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.
There is a growing interest in the use of granulocytic surface markers for the diagnosis of some inherited and acquired disorders, such as Shwachman-Diamond syndrome and myelodysplastic syndromes. Understanding the impact of physiologic factors, such as age, gender, pregnancy, race, and stress on granulocytic surface markers is essential for appropriate interpretation of results. Some surface markers show marked variations at the very early and the very late stages in life. Fetal granulocytes tend to have a lower expression of CD11b, CD11c, CD18, and CD32. Term neonatal granulocytes are frequently associated with a lower expression of CD10, CD11b, CD13, CD33, and CD62L and a higher expression of CD55 and CD64. Elderly individuals have shown a higher expression of CD64. Pregnancy is associated with temporary changes in granulocytic surface markers, such as a lower expression of CD16 and a higher CD64, partially mimicking an inflammatory response. Stress also has an impact on some surface markers, particularly adhesion molecules, such as CD62L and CD54. These factors need to be taken in consideration for the optimal interpretation of granulocytic surface marker studies.
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