Molecular and cellular dynamics of measurable residual disease progression in myelodysplastic syndromes
Year: 2025
Type: preprint
Abstract: Cancer relapse after treatment invariably proceeds from the persistence and progression of measurable residual disease (MRD), an ultrasmall malignant population. Despite the poor prognostic impact established by increasingly sensitive MRD detection methods, the molecular pathways defining MRD remain unknown. To identify the unique features of MRD and the molecular forces shaping its progression, we performed single-cell multi-omic profiling on DNA, RNA and protein layers for a longitudinal patient cohort with relapsed myelodysplastic syndromes (MDS) after stem cell transplantation (SCT), the only curative modality for MDS. We provide a comprehensive molecular portrait of MRD cells with novel markers, shared across genetically heterogeneous patients. MDS relapse after SCT manifested universally with marked phenotypic evolution. Genotype and phenotype analyses revealed MRD progression as a dynamic, evolutionary process rather than a static expansionary one, driven by both subclonal sweeping and cell state transitions. Malignant cells adapted to infiltrating T cells by rewiring IFN-γ responses to activate a key immunoevasive pathway. Our study demonstrates the power of longitudinal, single-cell multi-omic analysis for identifying, tracking, and understanding MRD cells, opening new avenues to target MRD persistence and progression.
Authors: Yu-Hsiang Chen, Timothy Bi, Minhang Xu, Jaehyun Lee, Wesley S. Lu, Mengchuan Zhuang, Alejandro Marinos Velarde, Dustin McCurry, Hui Yang, Gheath Al-Atrash, Gabriela Rondon, Elizabeth Shpall, Fatima Zahra Jelloul, Frances N. Cervoni-Curet, Sassine Ghanem, Celine Kerros, Priya Koppikar, Jeffrey Molldrem, Guillermo Garcia-Manero, Ankit Patel, Pavan Bachireddy
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Damon Runyon Cancer Research Foundation, Pharmaceutical Research and Manufacturers of America Foundation, Cancer Prevention and Research Institute of Texas, Edward P. Evans Foundation, Andrew Sabin Family Foundation, Break Through Cancer, University of Texas MD Anderson Cancer Center, National Cancer Institute
OpenAlex ID: W4415345478