AccScience Publishing / EJMO / Online First / DOI: 10.36922/EJMO026020009
Submit to EJMO
Cite this article
2
Download
45
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Expression profiling elucidates the mechanisms of deferasirox-mediated sensitization in venetoclax-resistant acute myeloid leukemia

Xicen Liu1 ,  Lin Liu1 ,  Li Wang1*
Show Less
1 Department of Hematology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
EJMO, 026020009 https://doi.org/10.36922/EJMO026020009
Received: 5 January 2026 | Revised: 20 February 2026 | Accepted: 11 March 2026 | Published online: 4 June 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Download PDF
XML
Cite
Abstract

Introduction: Resistance to the B-cell lymphoma 2 inhibitor venetoclax (VEN) poses a significant therapeutic challenge in acute myeloid leukemia (AML).

Objective: This study systematically investigates the molecular mechanisms through which the iron chelator deferasirox (DFX) overcomes VEN resistance in AML.

Methods: We utilized an AML cell line model treated with VEN, the iron chelator DFX, or their combination (VEN+DFX). Integrated transcriptomic profiling by RNA sequencing, combined with weighted gene co-expression network analysis and functional bioinformatics, was applied to elucidate the molecular mechanisms underlying DFX-induced sensitization. The findings were subsequently evaluated in SKM1- and MOLM-13-derived xenograft models.

Results: Transcriptomic profiling confirmed that VEN treatment enriches a population of cells exhibiting a transcriptional signature associated with enhanced oxidative phosphorylation (OXPHOS). The addition of DFX to VEN specifically reversed this signature, resulting in the downregulation of key electron transport chain (ETC) components. Mechanistically, DFX, via iron chelation, disrupts the assembly and function of iron-dependent ETC complexes. This disruption leads to mitochondrial dysfunction, characterized by energetic crisis and oxidative stress, thereby abolishing the compensatory survival mechanism and reinstating potent cell death. Furthermore, DFX also induced a differentiation-associated signature through upregulation of CEBPB/CEBPD and activated terminal stress-response pathways.

Conclusion: This study established a novel metabolic targeting strategy to overcome VEN resistance. We demonstrated that VEN induces a state of compensatory OXPHOS dependency, which is then selectively vulnerable to iron chelation via DFX. This “induce-and-target” approach leverages the acquired metabolic vulnerability of resistant cells, offering a compelling mechanistic rationale for the VEN+DFX combination. Our findings suggest OXPHOS dependency as a potential predictive biomarker and outline a translatable therapeutic framework for the treatment of VEN-resistant AML.

Keywords
Acute myeloid leukemia
Venetoclax resistance
Deferasirox
Iron chelation
Oxidative phosphorylation
Metabolic vulnerability
Mitochondrial metabolism
Funding
This study was supported by the National Natural Sciences Foundation of China (grant no. 82070130).
Conflict of interest
The authors declare no conflicts of interest.
References
  1. Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373(12):1136-1152. doi: 10.1056/nejmra1406184

 

  1. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020;383(7):617-629. doi: 10.1056/nejmoa2012971

 

  1. Wei AH, Montesinos P, Ivanov V, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137-2145. doi: 10.1182/blood.2020004856

 

  1. Guinan K, Mathurin K, Au Y, et al. Venetoclax in Combination with Azacitidine for the Treatment of Newly Diagnosed Acute Myeloid Leukemia: A Canadian Cost- Utility Analysis. Curr Oncol. 2022;29(10):7524-7536. doi: 10.3390/curroncol29100592

 

  1. Stevens BM, Jones CL, Pollyea DA, et al. Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells. Nat Cancer. 2020;1(12):1176-1187. doi: 10.1038/s43018-020-00126-z

 

  1. Chua CC, Roberts AW, Reynolds J, et al. Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy. J Clin Oncol. 2020;38(30):3506-3517. doi: 10.1200/jco.20.00572

 

  1. Rouault TA. Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci. 2013;14(8):551-564. doi: 10.1038/nrn3453

 

  1. Callens C, Coulon S, Naudin J, et al. Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia. J Exp Med. 2010;207(4):731-750. doi: 10.1084/jem.20091488

 

  1. Wu D, Li M, Hong Y, et al. Integrated stress response activation induced by usnic acid alleviates BCL-2 inhibitor ABT-199 resistance in acute myeloid leukemia. J Adv Res. 2025;74:621-635. doi: 10.1016/j.jare.2024.10.003

 

  1. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9(1):559. doi: 10.1186/1471-2105-9-559

 

  1. Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2020;49(D1):D605-D612. doi: 10.1093/nar/gkaa1074

 

  1. Lobry C, Oh P, Aifantis I. Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think. J Exp Med. 2011;208(10):1931-1935. doi: 10.1084/jem.20111855

 

  1. Wang Y, Krivtsov AV, Sinha AU, et al. The Wnt/β-Catenin Pathway Is Required for the Development of Leukemia Stem Cells in AML. Science. 2010;327(5973):1650-1653. doi: 10.1126/science.1186624

 

  1. Zhang B, Li M, McDonald T, et al. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt–β-catenin signaling. Blood. 2013;121(10):1824-1838.doi: 10.1182/blood-2012-02-412890

 

  1. Friedman AD. C/EBPα in normal and malignant myelopoiesis. Int J Hematol. 2015;101(4):330-341. doi: 10.1007/s12185-015-1764-6

 

  1. Hirai H, Zhang P, Dayaram T, et al. C/EBPβ is required for “emergency” granulopoiesis. Nat Immunol. 2006;7(7):732- 739. doi: 10.1038/ni1354

 

  1. Hirst J. Mitochondrial Complex I. Annu Rev Biochem. 2013;82(1):551-575. doi: 10.1146/annurev-biochem-070511-103700

 

  1. Lill R. Function and biogenesis of iron–sulphur proteins. Nature. 2009;460(7257):831-838. doi: 10.1038/nature08301

 

  1. Ow YLP, Green DR, Hao Z, Mak TW. Cytochrome c: functions beyond respiration. Nat Rev Mol Cell Biol. 2008;9(7):532-542. doi: 10.1038/nrm2434

 

  1. Sazanov LA. A giant molecular proton pump: structure and mechanism of respiratory complex I. Nat Rev Mol Cell Biol. 2015;16(6):375-388. doi: 10.1038/nrm3997

 

  1. Jones CL, Stevens BM, D’Alessandro A, et al. Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells. Cancer Cell. 2018;34(5):724-740.e4. doi: 10.1016/j.ccell.2018.10.005

 

  1. Farge T, Saland E, de Toni F, et al. Chemotherapy- Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism. Cancer Discov. 2017;7(7):716-735. doi: 10.1158/2159-8290.cd-16-0441

 

  1. Lagadinou ED, Sach A, Callahan K, et al. BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem Cells. Cell Stem Cell. 2013;12(3):329-341. doi: 10.1016/j.stem.2012.12.013

 

  1. DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2(5):e1600200. doi: 10.1126/sciadv.1600200

 

  1. Kalkavan H, Green DR. MOMP, cell suicide as a BCL-2 family business. Cell Death Differ. 2017;25(1):46-55. doi: 10.1038/cdd.2017.179

 

  1. Costa-Mattioli M, Walter P. The integrated stress response: From mechanism to disease. Science. 2020;368(6489):eaat5314. doi: 10.1126/science.aat5314

 

  1. Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol. 2020;21(8):421-438. doi: 10.1038/s41580-020-0250-z

 

  1. Hino C, Pham B, Park D, et al. Targeting the Tumor Microenvironment in Acute Myeloid Leukemia: The Future of Immunotherapy and Natural Products. Biomedicines. 2022;10(6):1410. doi: 10.3390/biomedicines10061410

 

  1. Menter T, Tzankov A. Tumor Microenvironment in Acute Myeloid Leukemia: Adjusting Niches. Front Immunol. 2022;13:811144. doi: 10.3389/fimmu.2022.811144

 

  1. Pizzimenti C, Fiorentino V, Ruggeri C, et al. Autophagy Involvement in Non-Neoplastic and Neoplastic Endometrial Pathology: The State of the Art with a Focus on Carcinoma. Int J Mol Sci. 2024;25(22):12118. doi: 10.3390/ijms252212118

 

  1. Golovkine GR, Roberts AW, Morrison HM, et al. Author Correction: Autophagy restricts Mycobacterium tuberculosis during acute infection in mice. Nat Microbiol. 2024;9(7):1899. doi: 10.1038/s41564-024-01605-0

 

  1. Deretic V. Autophagy in Tuberculosis. Cold Spring Harb Perspect Med. 2014;4(11):a018481. doi: 10.1101/cshperspect.a018481

 

  1. Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25(3):486-541. doi: 10.1038/s41418-017-0012-4

 

  1. Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017;171(2):273-285. doi: 10.1016/j.cell.2017.09.021
Share
Back to top
Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept