A CEBPB/IL-1β/TNF-α feedback loop drives drug resistance to venetoclax and MDM2 inhibitors in monocytic leukemia
Abstract
Abstrat MDM2 inhibitors are promising therapeutics for acute myeloid leukemia (AML) with wild-type TP53. Through an integrated analysis of functional genomic data from primary patient samples, we found that an MDM2 inhibitor, idasanutlin, like venetoclax, is ineffective against monocytic leukemia (French-American-British [FAB] subtype M4/M5). To dissect the underlying resistance mechanisms, we explored both intrinsic and extrinsic factors. We found that monocytic leukemia cells express elevated levels of CEBPB, which promote monocytic differentiation, suppress CASP3 and CASP6, and upregulate MCL1, BCL2A1, and the interleukin (IL-1)/tumor necrosis factor alpha (TNF-α)/NF-κB pathway members, thereby conferring drug resistance to a broad range of MDM2 inhibitors, BH3 mimetics, and venetoclax combinations. In addition, aberrant monocytes in M4/M5 leukemia produce elevated levels of IL-1 and TNF-α, which promote monocytic differentiation and upregulate inflammatory cytokines and receptors, thereby extrinsically protecting leukemia blasts from venetoclax and MDM2 inhibition. Interestingly, IL-1β and TNF-α only increase CEBPB levels and protect M4/M5 cells from these drugs but not M0/M1 leukemia cells. Treatment with venetoclax and idasanutlin induces compensatory upregulation of CEBPB and the IL-1/TNF-α/NF-κB pathway independent of the FAB subtype, indicating drug-induced compensatory protection mechanisms. The combination of venetoclax or idasanutlin with inhibitors that block the IL-1/TNF-α pathway demonstrates synergistic cytotoxicity in M4/M5 AML. As such, we uncovered a targetable positive feedback loop that involves CEBPB, IL-1/TNF-α, and monocyte differentiation in M4/M5 leukemia and promotes both intrinsic and extrinsic drug resistance and drug-induced protection against venetoclax and MDM2 inhibitors.
Article Details
Authors (30)
Basil Allen
1Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Daniel Bottomly
Thomas Köhnke
3Division of Hematology, Department of Medicine, Cancer Institute and Institute of Stem Cell Biology and Regenerative Medicine, Stanford, CA
Anthony Wang
Hsin-Yun Lin
4Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Kara Johnson
5Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Isabel Kenna
1Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Anastatia Streltsova
1Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Emma Martin
Centre for Inflammation Research
Reid Chen
1Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Lindsey Savoy
1Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Nicola Long
1Oregon Health & Science University, Division of Hematologic Malignancies, Knight Cancer Institute, Portland, United States
Peter Ryabinin
2Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Stephen E. Kurtz
4Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Christopher A. Eide
5Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Amy Carlos
6Massively Parallel Sequencing Shared Resource, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Andy Kaempf
1Oregon Health & Science University, Division of Hematologic Malignancies, Knight Cancer Institute, Portland, United States
Tingting Liu
Cristina Tognon
1Oregon Health & Science University, Division of Hematologic Malignancies, Knight Cancer Institute, Portland, United States
Robert Searles
6Massively Parallel Sequencing Shared Resource, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Paul D. Piehowski
Sara J. C. Gosline
Pacific Northwest National Laboratory
Anupriya Agarwal
4OHSU Knight Cancer Institute, Portland, United States
Bill H. Chang
19Division of Pediatric Hematology and Oncology, Doernbecher Children's Hospital at Oregon Health & Science University, Portland, OR
Michelle Barton
1Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Brian J. Druker
Oregon Health & Science University, Portland, Oregon, United States
Shannon K. McWeeney
2Knight Cancer Institute, Oregon Health & Science University, Portland, OR
Ravindra Majeti
2Stanford University
Jeffrey W. Tyner
15Department of Cell, Developmental, and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR
Haijiao Zhang
College of Life and Health Sciences, Northeastern University