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

Authors :
Mónica del Rey González
Sohini Chakraborty
Jesús María Hernández-Sánchez
María Diez Campelo
Christopher Y. Park
Jesús María Hernández Rivas
Source :
Frontiers in Oncology, Vol 14 (2024)
Publication Year :
2024
Publisher :
Frontiers Media S.A., 2024.

Abstract

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.

Details

Language :
English
ISSN :
2234943X
Volume :
14
Database :
Directory of Open Access Journals
Journal :
Frontiers in Oncology
Publication Type :
Academic Journal
Accession number :
edsdoj.7fb6c7685b74917942b55da558c1fcc
Document Type :
article
Full Text :
https://doi.org/10.3389/fonc.2024.1438052