Portal de Periódicos da CAPES

BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies

2014; Springer Nature; Volume: 28; Issue: 8 Linguagem: Inglês

10.1038/leu.2014.44

1476-5551

James M. Bogenberger, Steven M. Kornblau, William E. Pierceall, Ryan Lena, Donald Chow, C-X Shi, Jeremy Mantei, Greg Ahmann, Ida Gonzales, Ashish Choudhary, Ricardo A. Valdez, John Camoriano, Veena Fauble, Rodger E. Tiedemann, Yongchang Qiu, Kevin R. Coombes, Michael H. Cardone, Esteban Braggio, Hongwei Yin, D. O. Azorsa, Ruben A. Mesa, A. Keith Stewart, Raoul Tibes,

RNA Interference and Gene Delivery

Synergistic molecular vulnerabilities enhancing hypomethylating agents in myeloid malignancies have remained elusive. RNA-interference drug modifier screens identified antiapoptotic BCL-2 family members as potent 5-Azacytidine-sensitizing targets. In further dissecting BCL-XL, BCL-2 and MCL-1 contribution to 5-Azacytidine activity, siRNA silencing of BCL-XL and MCL-1, but not BCL-2, exhibited variable synergy with 5-Azacytidine in vitro. The BCL-XL, BCL-2 and BCL-w inhibitor ABT-737 sensitized most cell lines more potently compared with the selective BCL-2 inhibitor ABT-199, which synergized with 5-Azacytidine mostly at higher doses. Ex vivo, ABT-737 enhanced 5-Azacytidine activity across primary AML, MDS and MPN specimens. Protein levels of BCL-XL, BCL-2 and MCL-1 in 577 AML patient samples showed overlapping expression across AML FAB subtypes and heterogeneous expression within subtypes, further supporting a concept of dual/multiple BCL-2 family member targeting consistent with RNAi and pharmacologic results. Consequently, silencing of MCL-1 and BCL-XL increased the activity of ABT-199. Functional interrogation of BCL-2 family proteins by BH3 profiling performed on patient samples significantly discriminated clinical response versus resistance to 5-Azacytidine-based therapies. On the basis of these results, we propose a clinical trial of navitoclax (clinical-grade ABT-737) combined with 5-Azacytidine in myeloid malignancies, as well as to prospectively validate BH3 profiling in predicting 5-Azacytidine response.