title: Imatinib and nilotinib induce apoptosis of chronic myeloid leukemia cells through a Bim-dependant pathway modulated by cytokines.
abstract: 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.
authors.affiliation: Laboratoire d'Hématologie, Hôpital du Haut Lévèque, Pessac, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Belloc
authors.forename: François
authors.initials: F
authors.lastname: Moreau-Gaudry
authors.forename: Maialen
authors.initials: M
authors.lastname: Uhalde
authors.forename: Laurie
authors.initials: L
authors.lastname: Cazalis
authors.forename: Marie
authors.initials: M
authors.lastname: Jeanneteau
authors.forename: Francis
authors.initials: F
authors.lastname: Lacombe
authors.forename: Vincent
authors.initials: V
authors.lastname: Praloran
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Mahon
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010879:Piperazines / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001549:Benzamides; D016207:Cytokines; D008565:Membrane Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib