Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells

• DOI: 10.1038/sigtrans.2017.12
• Publication Date: 2017-04-07T12:10:49Z
• Authors: Daniel A Luedtke; Xiaojia Niu; Yihang Pan; Jianyun Zhao; Shuang Liu; Holly Edwards; Kang Chen; Hai Lin; Jeffrey W Taub; Yubin Ge
• Keywords: 0303 health sciences; 03 medical and health sciences; Article

Abstract Acute myeloid leukemia (AML) is a serious disease. The 5-year survival rates remain frustratingly low (65% for children and 26% adults). Resistance to frontline chemotherapy (usually cytarabine) often develops; therefore new treatment modality needed. Bcl-2 family proteins play an important role in balancing cell apoptosis. antiapoptotic have been found be dysregulated AML. ABT-199, BH3 mimetic, was developed target protein Bcl-2. Although ABT-199 has demonstrated promising results, resistance occurs. Previous studies AML show that alone decreases the association of proapoptotic Bim with Bcl-2, but this compensated by increased prosurvival Mcl-1, stabilizing resulting ABT-199. In study, we investigated antileukemic activity Mcl-1-selective inhibitor A-1210477 combination cells. We synergistically induced apoptosis lines primary patient samples. synergistic induction decreased upon Bak, Bax knockdown. While also Mcl-1 levels, reduced binding Mcl-1. Our results demonstrate sequestration mechanism resistance, can abrogated combined A-1201477.