Single-cell multi-omics profiling reveals distinct patterns of clonal expansion and microenvironmental shifts associated with disease evolution in patients with Myelodysplastic Syndromes

作者：Matteo Zampini, E. Riva, N. Sompairac, G. Maggioni, Rita Antunes Dos Reis, Rosa Andres Ejarque, L. Crisafulli, Nicolas Derus, M. Tarozzi, C. Sala, P. Acha, Emili Cid Roldós, Elisabetta Sauta, L. Lanino, Alessia Campagna, G. Todisco, M. Ubezio, Antonio Russo, Francesco Pesce, Mattia Delleani, G. Asti, Denise Ventura, C. Tentori, Alessandro Buizza, Ivan Ferrari, Matteo Brindisi, Nicole Pinocchio, Elisa Calvetti, Nicla Manes, Chiara Milanesi, Mara Memoli, Federico Caretti, R. Xie, Lorea Chaparro, Caterina Mata, Armando Santoro, V. Santini, A. Zeidan, R. Komrokji, P. Guglielmelli, A. Vannucchi, G. Garcia-Manero, S. Colla, S. D'amico, Guido Sanguinetti, G. Castellani, Francesc Solé, S. Kordasti, F. Ficara, M. D. Della Porta · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-3830

Myelodysplastic Syndromes (MDS) present an increased risk of progression to Acute Myeloid Leukemia (AML). The complex interactions between neoplastic clone, bone marrow (BM) microenvironment and immune cells during disease evolution remain poorly understood. We used multi-omics single-cell approach to define patterns of clonal expansion and microenvironment shifts associated with MDS disease progression. We analyzed paired BM samples at diagnosis and at time of AML transformation from 20 MDS patients who had not received disease-modifying treatments before progression. Single-cell analysis was performed by CITE-seq, integrating transcriptomic and protein expression data from hematopoietic stem and progenitor cells (HSPC), myeloid, T and NK cells, in combination with single-cell genotyping (TAPESTRI). To study longitudinal dynamics of cell states, we projected each cell into gene expression space and quantified the fold-enrichment of transcriptionally similar cells between diagnosis and AML by k-nearest neighbor analysis. Differential gene/protein expression analyses were performed by linear mixed-effects models accounting for inter-patient variability. We identified two evolution patterns in HSPC compartment. In 9 patients (pts), progression was marked by emergence of novel HSPC clusters with leukemic stem cell (LSC)-like phenotype (absent/minimally detectable at diagnosis), showing upregulation of LSC markers (CD99, CD44) and immune evasion proteins (CD47, CD27...