Efficacy of a novel BCL-xL degrader, DT2216, in preclinical models of <i>JAK2</i>-mutated post-MPN AML
Abstract
Abstract Acute myeloid leukemia (AML) that evolves from myeloproliferative neoplasm (MPN) is known as post-MPN AML. Current treatments do not significantly extend survival beyond 12 months. B-cell lymphoma-extra large (BCL-xL) has been found to be overexpressed in leucocytes from patients with MPN, making it a potential therapeutic target. We investigated the role of BCL-xL in post-MPN AML and tested the efficacy of DT2216, a platelet-sparing BCL-xL proteolysis-targeting chimera, in preclinical models of post-MPN AML. We found that BCL2L1, the gene encoding BCL-xL, is expressed at higher levels in patients with post-MPN AML than in those with de novo AML. Single-cell multiomics analysis revealed that leukemia cells harboring both MPN-driver and TP53 mutations exhibited higher BCL2L1 expression and elevated scores for leukemia stem cell, megakaryocyte development, and erythroid progenitor than wild-type cells. BH3 profiling confirmed a strong dependence on BCL-xL in post-MPN AML cells. DT2216 alone, or in combination with standard AML/MPN therapies, effectively degraded BCL-xL, reduced the apoptotic threshold, and induced apoptosis in post-MPN AML cells. DT2216 effectively eliminated viable cells in JAK2-mutant AML cell lines, induced pluripotent stem cell–derived hematopoietic progenitor cells, primary samples, and reduced tumor burden in cell line–derived xenograft model in vivo by degrading BCL-xL. DT2216, either as a single agent or in combination with azacytidine, effectively inhibited the clonogenic potential of CD34+ leukemia cells from patients with post-MPN AML. In summary, our data indicate that the survival of post-MPN AML is BCL-xL dependent, and DT2216 may offer therapeutic advantage in this high-risk leukemia subset with limited treatment options.
Article Details
Authors (24)
Zhe Wang
Anna Skwarska
Albert Einstein College of Medicine
Gowri Poigaialwar
1Albert Einstein College of Medicine, Cell Biology, Bronx, United States
Sovira Chaudhry
1Albert Einstein College of Medicine, Cancer Center, Bronx, United States
Alba Rodriguez-Meira
1Dana Farber Cancer Instititue, Department of Cancer Biology, Boston, United States
Pinpin Sui
6Department of Cell Systems and Anatomy, The University of Texas Health Science Center at San Antonio, San Antonio, TX
Emmanuel Olivier
1Icahn School of Medicine at Mount Sinai, New York, United States
Yannan Jia
1Department of Hematology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
Varun Gupta
Bragg Centre for Materials Research University of Leeds Leeds UK
Warren Fiskus
1The University of Texas MD Anderson Cancer Center, Houston, TX
Cassandra L. Ramage
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Guangrong Zheng
Alexandra Schurer
1Albert Einstein College of Medicine, Department of Cell Biology, Bronx, United States
Kira Gritsman
Eirini P. Papapetrou
Kapil Bhalla
2Division of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Daohong Zhou
Adam J. Mead
Medical Research Council (MRC) Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR, Biomedical Research Centre, University of Oxford, Oxford, United Kingdom; Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
Raajit K. Rampal
11Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
Jeffrey W. Tyner
15Department of Cell, Developmental, and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR
Hussein A. Abbas
M D Anderson Cancer Center, Houston, Texas, United States
Naveen Pemmaraju
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Qi Zhang Tatarata
7Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, NY
Marina Konopleva