Real‐world, multi‐omics validation of the clinical relevance of molecular taxonomy for myelodysplastic syndromes (MDS)
Giulia Maggioni, Gabriele Todisco, Elisabetta Sauta, Luca Lanino, Somedeb Ball, Jan P. Bewersdorf, Tariq Kewan, Najla H. Al Ali, Pierre Fenaux, Uwe Platzbecker, Valeria Santini, Zhuoer Xie, Andrew M. Brunner, Andrew T. Kuykendall, John M. Bennett, Rena Buckstein, Rafael Bejar, Hetty E. Carraway, Amy E. DeZern, Elizabeth A. Griffiths, Stephanie Halene, Robert P. Hasserjian, Alan F. List, Sanam Loghavi, Olatoyosi Odenike, Eric Padron, Mrinal M. Patnaik, Gail J. Roboz, Maximilian Stahl, Mikkael A. Sekeres, David P. Steensma, Michael R. Savona, Justin Taylor, Mina L. Xu, David A. Sallman, Stephen D. Nimer, Christopher S. Hourigan, Andrew H. Wei, Alessia Campagna, Marta Ubezio, Elena Riva, Denise Ventura, Nicole Pinocchio, Matteo Zampini, Alessandro Buizza, Antonio Russo, Francesco Pesce, Saverio D'Amico, Gianluca Asti, Mattia Delleani, Erica Travaglino, Cristina A. Tentori, Ivan Ferrari, Alessandra Crespi, Giulia Figini, Maria Di Matteo, Matteo Brindisi, Nicla Manes, Chiara Milanesi, Laura Crisafulli, Francesca Ficara, Gastone Castellani, Uma M. Borate, Fabio Efficace, Steven D. Gore, Tae K. Kim, Maria Diez‐Campelo, Arjan A. van de Loosdrecht, Navel Daver, Maria Rozman, Alberto Orfao, Sa A. Wang, Kathryn Foucar, Marcelo Iastrebner, Phillip Scheinberg, Yasushi Miyazaki, Yazan F. Madanat, Aref Al‐Kali, Moshe Mittelmann, Thomas Cluzeau, Lionel Ades, Ulrich Germing, Guillermo Garcia‐Manero, Shahram Kordasti, Torsten Haferlach, Amer M. Zeidan, Rami S. Komrokji, Matteo G. Della Porta,Abstract
Myelodysplastic syndromes (MDS) are clinically and biologically diverse disorders, emphasizing the need for personalized treatment approaches. The International Working Group for Prognostication of MDS (IWG_PM) recently introduced a molecular classification, referred to as the MDS taxonomy, that categorizes patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at TP53 and TET2 loci. This study sought to validate and enhance the clinical relevance of the MDS taxonomy by analyzing a large retrospective cohort ( n = 5136) and transcriptomic data from a prospective cohort ( n = 477). The taxonomy successfully identified subgroups with distinct clinical characteristics and disease progression patterns. However, incorporating gene interactions from taxonomy subgroups did not improve the prognostic performance of the Molecular International Prognostic Scoring System (IPSS‐M). We further assessed whether the taxonomy could guide management in patients receiving disease‐modifying therapies. Except for the “ TP53 ‐complex” subgroup, taxonomy classifications were not predictive of hypomethylating agent response or transplant outcomes. Nonetheless, they correlated with overall survival, suggesting that while both IPSS‐M and the taxonomy capture disease biology, other non‐genetic factors may influence treatment response. RNA sequencing confirmed the biological distinctiveness of the taxonomy groups. Transcriptomic profiling of CD34+ bone marrow cells revealed unique, homogeneous gene expression patterns, particularly within the AML‐like, bi TET2 , SF3B1 , and TP53 ‐complex subgroups. Further integration of multi‐omics data may refine MDS classification, improving clinical decision‐making and guiding the development of targeted therapies.