2. Academic Validation
  3. An Isoform-Specific RUNX1C-BTG2 Axis Governs AML Quiescence and Chemoresistance

An Isoform-Specific RUNX1C-BTG2 Axis Governs AML Quiescence and Chemoresistance

  • Blood Cancer Discov. 2025 Sep 3;6(5):464-483. doi: 10.1158/2643-3230.BCD-24-0327.
Cuijuan Han 1,  Zhiping Zhang 2,  Edie I Crosse 3,  Sogand Sajedi 4,  Bin Lu 5,  Xiyue Wang 1 6,  Sadik Karma 1 6,  Mitch Kostich 1,  Sakthi Harini Rajendran 1 6,  Dylan B Udy 3,  Steven Chen 2,  Alexander Arnuk 1,  Abimbola Eunice Lawal 1,  Kayla R Koenig 1,  Meryl McKenna 1,  Patrick K Reville 4,  Hussein A Abbas 4,  Omar Abdel-Wahab 7,  Pedro Miura 2 8,  Robert K Bradley 3 9,  Eric Wang 1 2 8
Affiliations

Affiliations

  • 1 The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
  • 2 Department of Genetics and Genome Sciences, UConn Health, Farmington, Connecticut.
  • 3 Public Health Sciences and Basic Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • 4 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 5 Sanford Burnham Prebys Medical Discovery Institute, San Diego, California.
  • 6 Graduate Program in Genetics and Development, UConn Health, Farmington, Connecticut.
  • 7 Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 8 Institute for Systems Genomics, University of Connecticut Health Center, Farmington, Connecticut.
  • 9 Department of Genome Sciences, University of Washington, Seattle, Washington.
PMID: 40632085 DOI: 10.1158/2643-3230.BCD-24-0327
Abstract

Aberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet their role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in patients with AML before therapy and at relapse after chemotherapy and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long-isoform RUNX1C through its alternative distal promoter. The unique N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. BTG2 promoted rRNA deadenylation, resulting in decreased mRNA expression and stability. Deletion of rRNAs increased cellular quiescence. Moreover, RNA-based targeting of RUNX1C reactivated quiescent leukemia cells and enhanced chemotherapy efficacy. These findings delineated an isoform-specific transcriptional circuit that governed chemotherapy response, providing a potential therapeutic strategy to mitigate AML recurrence.

Significance: This study identifies RUNX1C as a contributor to AML chemoresistance and an inducer of quiescence through BTG2. Targeting RUNX1C with RNA-based approaches disrupts this state and improves chemotherapy response, highlighting RUNX1C inhibition as a promising strategy to overcome resistance and enhance treatment efficacy in AML.

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