C053 | Real-world, Multi-omics Validation of the Clinical Relevance of Molecular Taxonomy for Myelodysplastic Syndromes. an International Study on Behalf of Genomed4all, Synthema and Icmds Consortiums
Year: 2025
Type: article
Abstract: Myelodysplastic syndromes (MDS) are clinically and biologically heterogeneous disorders, highlighting the need for personalized treatment strategies. The IWG_PM has recently proposed a molecular classification—referred to as the MDS taxonomy—which stratifies patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at the TP53 and TET2 loci. This study aimed to validate and extend the clinical utility of the MDS taxonomy in clinical decision-making process by analyzing a large retrospective cohort (n = 5,136) and transcriptomic data from a prospective cohort (n = 477). We confirmed that MDS taxonomy identifies subgroups with distinct clinical features and disease trajectories. The IPSS-M outperformed MDS taxonomy in predicting patients’ clinical outcomes. Furthermore, gene interactions defined by MDS subgroups did not significantly improve the prognostic accuracy of conventional models. We also examined whether MDS taxonomy could provide additional insights into managing patients receiving disease-modifying therapies. With the exception of the “TP53-complex” subgroup, the MDS taxonomy was not predictive of response to hypomethylating agents nor effective in identifying patients at high risk of transplant failure. RNA sequencing was used to validate the biological distinctiveness of MDS taxonomy groups. A random forest-based classification algorithm was applied to predict MDS taxonomy from differentially expressed genes. The algorithm’s accuracy varied across subgroups, with recall rates of 94%, 88%, 75%, and 71% for AML-like, SF3B1, biTET2, and TP53-complex groups, respectively. Classification accuracy was notably lower for other subcategories. To explore the biological significance of these transcriptomic signatures, we performed gene set enrichment analysis. Significant enrichment of gene ontology terms was observed only in the SF3B1, biTET2 and TP53-complex subgroups. SF3B1 MDS exhibited strong upregulation of genes involved in erythroid differentiation; biTET2 patients showed down-regulation of innate immune response mediated by Toll like receptor, IRAK4, MyD88/NFKB; TP53-complex subgroup showed specific overexpression of genes related to NOTCH and IFN-gamma signaling pathways Further research integrating multi-omics approaches is needed to develop a mechanistic MDS classification that could improve clinical decision-making and inform novel therapeutic strategies.
Authors: G. Maggioni, G. Todisco, E. Sauta, L. Lanino, S. Ball, Jp Bewersdorf, T Kewan, Nh Al Ali, P. Fenaux, U Platzbecker, V. Santini, Z Xie, AM. Brunner, At Kuykendall, JM. Bennett, R. Buckstein, R. Bejar, He Carraway, Ae Dezern, Ea Griffiths, S. Halene, Rp Hasserjian, Af List, S. Loghavi, O Odenike, E. Padron, MM. Patnaik, Gj Roboz, Maximilian Stahl, Ma Sekeres, Dp Steensma, Mr Savona, J Taylor, Ml Xu, Da Sallman, Sd Nimer, Cs Hourigan, Ah Wei, A. Campagna, M. Ubezio, E. Riva, D. Ventura, N. Pinocchio, M. Zampini, A. Buizza, A. Russo, F. Pesce, G. Asti, M. Delleani, E. Travaglino, Ca Tentori, I. Ferrari, A. Crespi, G. Figini, M. Di Matteo, M. Brindisi, L. Crisafulli, F. Ficara, G. Castellani, UM. Borate, F. Efficace, Sd Gore, Tk Kim, Aa Van De Loosdrecht, N. Daver, M. Rozman, A. Orfao, Sa Wang, K Foucar, M. Iastrebner, P. Scheinberg, Y Miyazaki, M. Mittelmann, T Cluzeau, L. Ades, U Germing, S. Kordasti, T Haferlach, AM. Zeidan, Rs Komrokji, Mg Della Porta.
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7094976630
FWCI:
Cites:
Cited by:
Related to: