Translational Research at ASH 2025 Illuminate Resistance, Risk Stratification in MCL

In this interview, Michael Wang, MD, discusses translational research from ASH 2025 that could impact MCL, a rare disease representing only about 6% of lymphomas. He emphasizes the significance of generating robust translational data in such a small patient population, particularly given the challenges of sample collection even at major academic centers.

The first study Wang highlights describes the development of an epigenetic signature capable of predicting clinical outcomes in MCL. He praises the investigators for assembling an adequate number of patient samples to perform meaningful analyses in a rare lymphoma and for successfully linking molecular features to prognosis.

Wang underscores that this work exemplifies high-quality translational research, bridging laboratory science and clinical care. He suggests that beyond risk stratification, such epigenetic signatures may ultimately identify driver events that can be leveraged as biomarkers or therapeutic targets. While the abstract format limits the depth of data presented, Wang anticipates that future full publications may reveal even more clinically actionable insights.

The second abstract focuses on drug-tolerant persister (DTP) cells, a resistance mechanism more commonly described in solid tumors but now characterized in MCL. Drawing on work from his own laboratory, Wang explains how prolonged exposure to targeted agents—including BTK inhibitors and monoclonal antibodies—can induce a population of enlarged, slow-cycling cells that survive therapy. These DTP cells display reversible drug tolerance: when the treatment pressure is removed, they revert to drug-sensitive states. Molecular analyses revealed that DTP cells possess stem cell–like properties, increased RNA biogenesis, and metabolic reprogramming of the TCA cycle, providing a biological framework for their survival.

Together, Wang notes, these studies stand out for moving beyond clinical efficacy to address why therapies succeed or fail, offering critical insights that could inform future biomarkers, combination strategies, and resistance-prevention approaches in MCL.