Editor’s Note: The 30th Congress of the European Hematology Association (EHA 2025) was held from June 12 to 15 in Milan, Italy. As one of the world’s leading hematology meetings, this year’s event spotlighted the latest advances across hematologic subspecialties, featuring cutting-edge approaches in diagnosis and treatment, along with new findings in both clinical and translational research. Among the studies presented, a research project led by Professor Jian Hou from Renji Hospital, Shanghai Jiao Tong University School of Medicine, was selected for an oral presentation (Abstract S188). This study sheds light on the critical role of non-coding enhancer-type extrachromosomal circular DNA (eccDNA), specifically eccANKRD28, in the development of drug resistance in multiple myeloma (MM). Oncology Frontier – Hematology Frontier spoke with Prof. Hou onsite for an in-depth discussion of this work.Oncology Frontier – Hematology Frontier: Your team’s oral presentation at EHA 2025 highlights the role of eccANKRD28, a non-coding enhancer-type eccDNA, in the development of resistance in multiple myeloma. What is the significance of this finding, and how might it change our understanding of MM treatment?
Prof. Jian Hou: Multiple myeloma remains an incurable disease, with treatment resistance posing a major challenge. Over time and with multiple lines of therapy, myeloma cells inevitably develop resistance to existing drugs. The mechanisms behind this resistance are highly complex.
Our study approached this issue from a novel angle—examining extrachromosomal circular DNA (eccDNA). These DNA fragments originate from damaged chromosomes and were traditionally thought to be biologically inert. However, we discovered that some of them, such as eccANKRD28, actually possess enhancer-like activity. They can regulate gene transcription in tumor cells, modulate cellular metabolism, and ultimately contribute to drug resistance. This insight opens a new window into how resistance to chemotherapy and targeted agents such as lenalidomide and bortezomib develops, and represents a significant innovation in the field.
Oncology Frontier – Hematology Frontier: Your data suggest that eccANKRD28 copy number at diagnosis correlates with patient prognosis and biomarkers. Do you believe eccANKRD28 could serve as a novel liquid biopsy marker for risk stratification or treatment monitoring? What are the current technical limitations?
Prof. Jian Hou: eccDNA fragments arise when chromosomal DNA is damaged, and while normal cells also produce some eccDNA, tumor cells—including myeloma cells—generate much larger and more specific quantities. In our study, we observed that eccANKRD28 levels differed significantly between malignant plasma cells and normal plasma cells. This makes it a promising candidate as a biomarker for drug resistance in MM.
However, this potential still requires rigorous validation through large-scale clinical sample testing. Technical challenges include the sensitivity and specificity of eccDNA detection, especially in blood samples. We’re continuing to explore this avenue, aiming to translate our findings into a reliable and practical clinical tool.
Oncology Frontier – Hematology Frontier: Your study leveraged multi-omics technologies like Circle-seq, scATAC-seq, and CUT&Tag. How did this multi-dimensional approach enhance your ability to identify functional non-coding eccDNA?
Prof. Jian Hou: Multi-omics techniques—spanning genomics, transcriptomics, and proteomics—offer powerful high-throughput and high-resolution capabilities. These tools allowed us to dissect the role of eccANKRD28 from multiple biological angles.
By integrating Circle-seq for eccDNA profiling, scATAC-seq for chromatin accessibility, and CUT&Tag for epigenetic mapping, we were able to precisely characterize the enhancer function of eccANKRD28 and understand its impact on drug resistance to bortezomib and lenalidomide in myeloma cells. This comprehensive approach not only enriched our understanding of eccANKRD28’s biological activity but also provided compelling evidence of its key role in resistance mechanisms.
Oncology Frontier – Hematology Frontier: Given that CRISPR-mediated regulation of eccANKRD28 appears to influence treatment sensitivity, do you see this pathway as a potential therapeutic target? What is the current stage of drug development or gene-editing strategies targeting this mechanism?
Prof. Jian Hou: Through a combination of in vitro cell culture, multi-omics screening, and in vivo animal models, we’ve confirmed that eccANKRD28 functions as an enhancer contributing to drug resistance in MM cells. This lays a foundation for future therapeutic interventions targeting this pathway.
Currently, our team is expanding this work to develop strategies aimed at reversing drug resistance by targeting eccANKRD28. This includes exploring gene editing via CRISPR technologies and investigating possible small-molecule inhibitors. While still in the early stages, our goal is to translate these findings from bench to bedside, ultimately offering new hope for patients facing treatment-resistant disease.
Expert Profile
Prof. Jian Hou Chief Physician, Renji Hospital, Shanghai Jiao Tong University School of Medicine
- Member, International Myeloma Working Group (IMWG)
- Standing Committee Member, Hematology Branch, Chinese Medical Association
- Standing Committee Member, Hematologic Oncology Committee, Chinese Anti-Cancer Association
- Standing Committee Member, Hematology and Oncology Committees, Chinese Medical Doctor Association
- Standing Committee Member, Chinese Lymphoma Alliance
- Committee Member, Experimental Hematology Branch, Chinese Association for Pathophysiology
- Standing Committee Member, Hematoimmunology Branch, Chinese Society for Immunology
- Chair, Hematoimmunology Committee, Shanghai Immunology Society
- Chair, Hematology Branch, Shanghai Medical Association
- Vice Chair, Clinical Research Committee, China Pharmaceutical Innovation and Research Development Association
