Article Dans Une Revue Experimental Hematology Année : 2012

ABT-737 increases tyrosine kinase inhibitor–induced apoptosis in chronic myeloid leukemia cells through XIAP downregulation and sensitizes CD34+ CD38− population to imatinib

Kelly Airiau
  • Fonction : Auteur
François-Xavier Mahon
  • Fonction : Auteur
  • PersonId : 936617
  • IdRef : 059378417
Marina Josselin
  • Fonction : Auteur
Marie Jeanneteau
Francis Belloc
  • Fonction : Auteur

Résumé

Chronic myeloid leukemia (CML) tumorigenicity is driven by the oncogenic BCR-ABL tyrosine kinase. Specific tyrosine kinase inhibitors (TKI) have been designed and are now used for the treatment of CML. These TKI induce apoptosis in leukemic cells in a BIM-dependent mechanism. We hypothesized that an increase in BIM activity could sensitize CML cells to TKI. We blocked the anti-apoptotic proteins of the Bcl-2 family by using ABT-737, a Bcl-2 and Bcl-XL inhibitor. ABT-737 modified Bcl-2 protein interactions toward a pro-apoptotic phenotype. Its combination with TKI resulted in a strong synergism in CML cell lines. The association also induced a large decrease in X-linked inhibitor of apoptosis (XIAP), followed by caspase-3 activation. This XIAP decrease was due to post-translational events. The mitochondrial serine protease HtrA2/Omi was identified as being responsible for this off-target effect. Then, ABT-737 and TKI cooperate at several levels to induce apoptosis of CML cells lines, and the benefit of this association was also observed in CML hematopoietic progenitors. Interestingly, a lethal effect was also observed in the more immature CD34(+)CD38(-) TKI-insensitive population. Combination therapy might by an interesting strategy for the treatment of CML patients.

Domaines

Cancer

Dates et versions

hal-03155368 , version 1 (01-03-2021)

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Citer

Kelly Airiau, François-Xavier Mahon, Marina Josselin, Marie Jeanneteau, Béatrice Turcq, et al.. ABT-737 increases tyrosine kinase inhibitor–induced apoptosis in chronic myeloid leukemia cells through XIAP downregulation and sensitizes CD34+ CD38− population to imatinib. Experimental Hematology, 2012, 40 (5), pp.367-378.e2. ⟨10.1016/j.exphem.2012.01.004⟩. ⟨hal-03155368⟩

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