Low Plasma Citrate Levels and Specific Transcriptional Signatures Associated with Quiescence of CD34(+) Progenitors Predict Azacitidine Therapy Failure in MDS/AML Patients
Abstract
Epigenetic drugs, such as azacitidine (AZA), hold promise in the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), however, the mechanisms predicting the patients' response to AZA is not completely understood. Quiescence of hematopoietic CD34+ progenitors has been proposed as a predictive factor for AZA therapy failure in MDS/AML patients, but the interplay between CD34+ cell cycle status and their metabolic signature in a predisposition to AZA (non)responsiveness remains unclear.
Our data on patients with MDS or AML with myelodysplasia-related changes (AML-MRC) suggest that AZA-responders have actively cycling CD34+ cells poised for erythro-myeloid differentiation, with high metabolic activity controlling histone acetylation. Conversely, the patients who progressed early on AZA therapy revealed quiescence signature of their CD34+ cells, with signs of reduced metabolically-controlled acetylation of histones needed for transcription-permissive chromatin configuration.
Our study delineates plasma citrate levels and CD34+ cells' transcriptional signatures associated with cycling status and metabolic characteristics as factors predicting the response to AZA monotherapy in MDS/AML-MRC patients.