2. Academic Validation
  3. Rapid Transcription Dynamics Confers Cytarabine Resistance in Acute Myeloid Leukemia

Rapid Transcription Dynamics Confers Cytarabine Resistance in Acute Myeloid Leukemia

  • Blood Cancer Discov. 2026 Jul 1;7(4):624-641. doi: 10.1158/2643-3230.BCD-25-0317.
Goichi Tatsumi # 1,  Rajni Kumari # 1,  Yutaro Suzuki 1,  Shuting Li 1,  Russell Scharf 1,  Samuel J Taylor 1,  Sriram Sundaravel 1,  Amit Verma 2 3 4 5 6 7,  Justin C Wheat 1,  Ulrich Steidl 1 3 4 5 6 7 8
Affiliations

Affiliations

  • 1 Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York.
  • 2 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York.
  • 3 Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Montefiore Einstein, Bronx, New York.
  • 4 Blood Cancer Institute, Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York.
  • 5 Cancer Dormancy Institute, Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York.
  • 6 Department of Oncology, Albert Einstein College of Medicine, Montefiore Einstein, Bronx, New York.
  • 7 Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, New York.
  • 8 Department of Medicine, Albert Einstein College of Medicine, Montefiore Einstein, Bronx, New York.
  • # Contributed equally.
PMID: 42149820 DOI: 10.1158/2643-3230.BCD-25-0317
Abstract

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.

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