Rapid Transcription Dynamics Confers Cytarabine Resistance in Acute Myeloid Leukemia

Chemotherapy resistance remains a critical challenge in the treatment of patients with Cancer, including acute myeloid leukemia (AML). Although genetic alterations can contribute to resistance, the role of rapid-adaptive nongenetic mechanisms, particularly transcription dynamics, remains poorly understood. In this article, we demonstrate that short-term treatment of AML cells with the widely used chemotherapeutic cytarabine (AraC) leads to the rapid emergence of a cell population with significant RNA induction and increased AraC resistance in cell lines and primary patient samples. Mechanistically, transcriptomic and targeted high-resolution analysis of transcription dynamics using single-molecule RNA FISH revealed rapid induction of transcriptional dynamics and upregulation of key transcription factors (TF)-which we term "AraC rapid response TFs." Functionally, short-term pre- and cotreatment with RNA transcription inhibitors suppressed chemotherapy-induced RNA induction and prevented resistance acquisition in vitro and in vivo. Furthermore, CRISPR-mediated suppression of TFs PU.1 and GATA1 significantly attenuated AraC resistance. Our findings reveal a role of rapid-adaptive transcriptional dynamics in AML chemotherapy resistance.

Significance: This study reveals a role of rapid-adaptive transcriptional dynamics in AML chemotherapy resistance, highlighting master TFs as key regulators. These insights offer a pharmacologically accessible approach to potentially alleviate the major clinical problem of chemotherapy resistance.