BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies.
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.
Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
J M
JM
Bogenberger
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
S M
SM
Kornblau
Eutropics Pharmaceuticals, Cambridge, MA, USA.
W E
WE
Pierceall
Eutropics Pharmaceuticals, Cambridge, MA, USA.
R
R
Lena
Translational Genomics Research Institute, Phoenix, AZ, USA.
D
D
Chow
Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
C-X
CX
Shi
Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
J
J
Mantei
Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
G
G
Ahmann
Translational Genomics Research Institute, Phoenix, AZ, USA.
I M
IM
Gonzales
Translational Genomics Research Institute, Phoenix, AZ, USA.
A
A
Choudhary
Department of Lab Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA.
R
R
Valdez
Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
J
J
Camoriano
Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
V
V
Fauble
Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
R E
RE
Tiedemann
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Y H
YH
Qiu
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
K R
KR
Coombes
Eutropics Pharmaceuticals, Cambridge, MA, USA.
M
M
Cardone
Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
E
E
Braggio
Translational Genomics Research Institute, Phoenix, AZ, USA.
H
H
Yin
Translational Genomics Research Institute, Phoenix, AZ, USA.
D O
DO
Azorsa
Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
R A
RA
Mesa
Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
A K
AK
Stewart
Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
R
R
Tibes
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000502:physiology; D009196:Myeloproliferative Disorders / Q000188:drug therapy; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000502:physiology
C501332:ABT-737; D000964:Antimetabolites, Antineoplastic; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; D001374:Azacitidine; C579720:venetoclax