Molecular profiling of pre- and post- 5-azacytidine myelodysplastic syndrome samples identifies predictors of response

• Published in: Frontiers in oncology Vol. 14; p. 1438052
• Main Authors: González, Mónica Del Rey, Chakraborty, Sohini, Hernández-Sánchez, Jesús María, Diez Campelo, María, Park, Christopher Y, Hernández Rivas, Jesús María
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 23.09.2024
• Subjects: gene expression; hematopoietic stem/progenitor cells (HSPCs); mutations; myelodysplastic syndrome (MDS); Oncology; patient survival; prognosis; hematopoietic stem/progenitor cells (HSPCs); mutations; patient survival; myelodysplastic syndrome (MDS); prognosis; gene expression
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2024.1438052

Treatment with the hypomethylating agent 5-azacytidine (AZA) increases survival in high-risk (HR) myelodysplastic syndrome (MDS) patients, but predicting patient response and overall survival remains challenging. To address these issues, we analyzed mutational and transcriptional profiles in CD34+ hematopoietic stem/progenitor cells (HSPCs) before and following AZA therapy in MDS patients. AZA treatment led to a greater reduction in the mutational burden in both blast and hematological responders than non-responders. Blast and hematological responders showed transcriptional evidence of pre-treatment enrichment for pathways such as oxidative phosphorylation, MYC targets, and mTORC1 signaling. While blast non-response was associated with TNFa signaling and leukemia stem cell signature, hematological non-response was associated with cell-cycle related pathways. AZA induced similar transcriptional responses in MDS patients regardless of response type. Comparison of blast responders and non-responders to normal controls, allowed us to generate a transcriptional classifier that could predict AZA response and survival. This classifier outperformed a previously developed gene signature in a second MDS patient cohort, but signatures of hematological responses were unable to predict survival. Overall, these studies characterize the molecular consequences of AZA treatment in MDS HSPCs and identify a potential tool for predicting AZA therapy responses and overall survival prior to initiation of therapy.