A Role for Rapid Transcription Dynamics in Cytarabine Resistance in Acute Myeloid Leukemia [ATAC-seq]

While genetic alterations contribute to chemotherapy resistance, rapid-adaptive non-genetic mechanisms, particularly transcription dynamics, remain poorly understood. Given the role of cell-intrinsic transcriptional variability in cell fate decisions, understanding and targeting chemotherapy-induced changes in transcription dynamics could offer new strategies to prevent chemotherapy resistance.

In this study, we demonstrate that short-term treatment with the widely used chemotherapeutic cytarabine (AraC) leads to the rapid emergence of RNA-induced AML cells with increased AraC resistance in both cell lines as well as primary patient samples. Mechanistically, through global transcriptomic analyses and targeted high-resolution analysis of transcription dynamics using single-molecule RNA FISH, we found rapid induction of transcriptional dynamics and upregulation of key transcription factors (TFs) - which we term “AraC rapid response TFs (ARR-TFs)” and which include PU.1 and GATA1 – following chemotherapy treatment.