Single-Cell Multi-Omics Reveals Anticipated Erythroid Differentiation and Transcriptional Regulation in Differentiation Trajectories of SF3B1 - JAK2/MPL Mutated Cells in MDS/MPN-RS-T

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.3194-3194
• Main Authors: Zampini, Matteo, Todisco, Gabriele, Chiodi, Alice, Chiereghin, Chiara, Saba, Elena, Gandolfi, Francesco, Ventura, Denise, Pinocchio, Nicole, Crisafulli, Laura, Brindisi, Matteo, Campagna, Alessia, Termanini, Alberto, Lanino, Luca, Ubezio, Marta, Maggioni, Giulia, Russo, Antonio, Buizza, Alessandro, Sauta, Elisabetta, Asti, Gianluca, D'Amico, Saverio, Vallelonga, Veronica, Ghisletti, Serena ML, Mosca, Ettore, Ficara, Francesca, Della Porta, Matteo Giovanni
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-201085

BACKGROUND. Myelodysplastic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T) is a rare hematologic malignancy with an uncertain pathobiology. Previous studies have identified coexisting driver mutations in proliferative (JAK2/MPL) and dysplastic (SF3B1) genes, contributing to its mixed myelodysplastic/ myeloproliferative neoplasm phenotype (PMID: 38714876). Despite these findings, the effects of these simultaneous mutations on the biology of hematopoietic stem cells (HSCs) and their differentiation trajectories remain unclear. The increased risk of progression to acute myeloid leukemia (AML) in patients with both SF3B1 and JAK2/MPL mutations compared to those with only SF3B1 mutations, combined with the lack of consolidated therapies, makes this a subject of significant interest for identifying molecular mechanisms that could be targeted. The aim of this study is to investigate the effect of co-mutations on clonal dynamics, differentiation trajectories, and transcriptional processes at the single-cell level. METHODS: We used Target-seq (PMID: 30765193), a single-cell multiomics approach that combines genotyping and transcriptomics on bone marrow CD34+ cells from six MDS/MPN-RS-T patients, paired with 10X 3' scRNA-seq and scATAC-seq. RESULTS: Single-cell analysis revealed a significant increase in erythroid differentiation in cells carrying both driver mutations compared to wild-type (WT) cells and those with only the SF3B1 mutation (p