Abstract:
: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.
journal_name
Leukemiajournal_title
Leukemiaauthors
Bogenberger JM,Kornblau SM,Pierceall WE,Lena R,Chow D,Shi CX,Mantei J,Ahmann G,Gonzales IM,Choudhary A,Valdez R,Camoriano J,Fauble V,Tiedemann RE,Qiu YH,Coombes KR,Cardone M,Braggio E,Yin H,Azorsa DO,Mesa RA,Stedoi
10.1038/leu.2014.44subject
Has Abstractpub_date
2014-08-01 00:00:00pages
1657-65issue
8eissn
0887-6924issn
1476-5551pii
leu201444journal_volume
28pub_type
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