Tyrosine Kinase Inhibitor-Mediated Apoptosis Is Potentiated by FasL and Increased with IFN-α in Chronic Myeloid Leukemia

Abstract 4428 The Fas death receptor (CD95/TNFSFR6) conveys death and non-death signals through binding to its cognate ligand, FasL (CD95L) 1,2 . Fas is expressed constitutively in CD34 + cells of patients with chronic myeloid leukemia 3 . In order to explore the implication of Fas in CML patient9s response, we aimed at analyzing expression and function of Fas in the imatinib-sensitive human Bcr-abl+ Fas+ AR 230S cell line, and in its imatinib-resistant counterpart AR 230R. We analysed the Fas-mediated apoptosis of AR230S and showed that not only imatinib (Figure 1) but also nilotinib and dasatinib (data not shown) potentiate Fas-L mediated apoptosis. This potentiation is dose dependent (Figure 2). Interestingly, there is no potentiation of TKI-mediated apoptosis by FasL in the imatinib-resistant counterpart AR 230R which is Fas negative. The Fas knockdown with a lentivirus-expressing a FAS-shRNA in AR 230S was associated with a disappearance of potentiation effect, whereas the up regulation of Fas expression in AR230 S cell line using lentivirus-expressing human Fas (hFas) induced an emphasized potentiation effect confirming the pivotal role of Fas in the potentiation of TKI-mediated apoptosis. Notably, IFN-α is able to enhance expression of Fas on CD34 + cells from CML patients 3 . We thus explored the action of IFN-α on the Fas potentiation of TKI-mediated apoptosis. We observed that preincubation with IFN-α increased potentiation in a dose-dependant manner (Data not shown). In conclusion, our preliminary results demonstrate the pivotal role of Fas in the potentiation of TKI-mediated apoptosis and highlight the role of IFN-α in the design of CML treatments. Disclosures: Legros: Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau.