Circular RNA Culprit Behind Imatinib Failure in Leukemia Identified

Chronic myeloid leukemia was once a death sentence, but the arrival of imatinib, the first targeted cancer drug of its kind, transformed it into a manageable condition for most patients. Yet a stubborn minority of patients stop responding to the drug, and the molecular reasons behind that failure remain only partly understood. A new study published in Molecular Biology Reports by Xiaoxu Lan, Hang Sun, Yulong Mu and colleagues at Shandong Medical and Pharmaceutical University and collaborating institutions in China now adds a striking piece to that puzzle, pointing to a circular RNA molecule and the cell-cycle protein it controls as central drivers of imatinib resistance.

The research focuses on a protein called cell division cycle-associated protein 4, or CDCA4, a factor originally identified nearly a quarter century ago as a gene preferentially expressed in hematopoietic progenitors and mature blood cells. In recent years, CDCA4 has attracted growing attention in oncology. Pan-cancer analyses have flagged it as an oncogenic player in a range of human tumors, and separate studies have implicated it in bladder cancer progression through JAK/STAT signaling, in osteosarcoma development, and in radiotherapy resistance in colorectal cancer. What the new work adds is a detailed picture of how CDCA4 behaves in the specific context of chronic myeloid leukemia and its frontline therapy.

The team began with a broad computational sweep. A pan-cancer analysis revealed that high CDCA4 expression was significantly associated with shorter overall survival across multiple cancer types, establishing the protein as a plausible prognostic marker well before any leukemia-specific experiments were run. The investigators then turned to clinical material and laboratory models. Using quantitative real-time PCR, they measured CDCA4 levels in peripheral blood samples from chronic myeloid leukemia patients and in imatinib-resistant cell lines derived from the disease. In both settings, CDCA4 was upregulated, suggesting that the protein’s abundance rises precisely where drug resistance is the problem.

To test whether that correlation reflected causation, the researchers manipulated CDCA4 expression in leukemia cells and monitored the consequences. Cell proliferation assays based on the CCK-8 colorimetric method showed that forcing CDCA4 overexpression markedly enhanced resistance to imatinib and promoted the proliferation of chronic myeloid leukemia cells. In other words, simply raising the level of this one cell-cycle protein was enough to blunt the effect of the drug that has defined modern CML treatment. That result positions CDCA4 not as a passive bystander in resistant cells but as an active participant in the resistant phenotype.

The mechanistic heart of the study lies in what CDCA4 does once it is abundant. The team’s investigations indicated that CDCA4 is associated with hyperactivation of the AKT-mTOR signaling axis, a canonical growth and survival pathway that cancer cells frequently co-opt to evade stress and therapy. Alongside that hyperactivation, the researchers observed a concurrent suppression of basal autophagy, the cellular recycling process by which cells break down damaged components and survive metabolic hardship. The combination, the authors report, correlates with imatinib chemoresistance in chronic myeloid leukemia cells. This pairing is biologically coherent: AKT-mTOR signaling is a well-known negative regulator of autophagy, and prior work has shown that mTOR inhibition with compounds such as AZD2014 can alleviate BCR::ABL1-independent imatinib resistance by enhancing autophagy in resistant cells. The new findings slot CDCA4 into that same regulatory territory, upstream of the pathway shift that helps leukemic cells survive the drug.

Autophagy’s role in drug response has become one of the more contested questions in cancer biology, and the CML literature reflects that tension. Some studies have found that suppressing autophagy sensitizes leukemic cells to treatment, while others, including the mTOR-inhibition work referenced by this team, suggest that restoring autophagic flux helps resistant cells regain vulnerability. The new study comes down clearly on the side of autophagy as a tumor-suppressive process in this context: CDCA4-driven resistance travels with reduced basal autophagy, implying that leukemic cells which lose their recycling capacity, while simultaneously ramping up pro-survival AKT-mTOR signaling, are better equipped to withstand imatinib. Disentangling exactly how CDCA4 biases the balance between these two processes will be a task for future experiments, but the correlation the authors document is a concrete starting point.

Perhaps the most consequential discovery is what sits above CDCA4 in the regulatory hierarchy. Through molecular profiling, the team identified a circular RNA, hsa_circ_0029325, that governs CDCA4 expression levels. Circular RNAs are covalently closed loops of RNA generated by back-splicing, a form of non-canonical RNA processing that makes them unusually stable and resistant to degradation by exonucleases. Once dismissed as transcriptional noise, circular RNAs are now recognized as versatile regulators that can sponge microRNAs, interact with RNA-binding proteins, and in some cases even be translated into peptides. Their stability makes them attractive biomarkers, detectable in blood and other body fluids, and their regulatory reach makes them potential drug targets.

The connection between circ_0029325 and CDCA4 fits into a rapidly expanding catalog of circular RNA circuits implicated in drug resistance. Previous studies have linked circular RNAs to imatinib resistance through several routes: circ_SIRT1 has been shown to upregulate ATG12 and facilitate imatinib resistance by interacting with the splicing factor EIF4A3, circ_0080145 enhances resistance by regulating the miR-326/PPFIA1 axis, and hsa_circ_0058493 was identified as a biomarker of imatinib-resistant CML through microarray profiling. The supplementary data accompanying the new study add a further layer of mechanistic detail, showing that miR-503-5p, one of the microRNAs capable of targeting CDCA4, slows cell proliferation and increases imatinib sensitivity in the resistant K562-R cell line. Together these findings sketch a model in which circ_0029325 acts as a molecular sponge, sequestering CDCA4-targeting microRNAs such as miR-503-5p and thereby freeing CDCA4 to accumulate, hyperactivate AKT-mTOR signaling, dampen autophagy, and shield leukemic cells from imatinib.

The clinical implications are twofold. First, the circ_0029325-CDCA4-AKT axis offers a set of candidate biomarkers: measuring levels of the circular RNA, the protein, or downstream pathway activity could, in principle, help identify patients at risk of losing response before frank resistance emerges, allowing earlier switches to second- or third-generation tyrosine kinase inhibitors, which are already recommended in treatment algorithms for resistant or intolerant disease. Second, each node in the circuit is a potential therapeutic target. Antisense oligonucleotides or small interfering RNAs designed against circular RNAs are an active area of drug development, microRNA mimics have been explored as cancer therapeutics, and AKT and mTOR inhibitors are established pharmacological classes with oncology track records. A combination strategy that disrupts the circular RNA circuit while pharmacologically re-engaging autophagy could, the authors suggest, restore imatinib sensitivity in resistant cells.

Caveats remain, as they always do at this stage of translational research. The study’s clinical component rests on peripheral blood samples from patients at a single Chinese center, and the mechanistic work was performed largely in cell lines and animal models rather than in prospective patient cohorts. Whether circ_0029325 levels reliably predict resistance in a real-world monitoring setting, and whether intervening on the axis improves outcomes, will require validation studies with larger and more diverse populations. Still, the work is notable for connecting the dots across scales, from a pan-cancer survival analysis down to a specific circular RNA, its microRNA intermediaries, a cell-cycle protein, and the signaling and autophagy changes that ultimately determine whether a leukemia cell dies when imatinib arrives. For a disease in which the drug revolution is now more than two decades old, understanding why that revolution fails in some patients is one of the most important questions left in the field, and this study offers a concrete, testable answer to pursue.

Subject of Research: Circular RNA regulation of CDCA4 and the AKT-mTOR/autophagy axis in imatinib-resistant chronic myeloid leukemia

Article Title: Hsa_circ_0029325 drives imatinib resistance via the CDCA4/AKT axis in chronic myeloid leukemia

Article References: Lan, X., Sun, H., Mu, Y., Hou, X., Ti, C., Sun, W., Xie, S., Li, Y., & Sun, Y. (2026). Hsa_circ_0029325 drives imatinib resistance via the CDCA4/AKT axis in chronic myeloid leukemia. Molecular Biology Reports, 53(1), Article 1702. https://doi.org/10.1007/s11033-026-12904-6

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12904-6

Keywords: chronic myeloid leukemia, imatinib resistance, CDCA4, hsa_circ_0029325, circular RNA, AKT-mTOR signaling, autophagy, miR-503-5p, tyrosine kinase inhibitors, drug resistance, biomarkers, hematology