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

Authors

Cuijuan Han
Zhiping Zhang
Edie I Crosse
Sogand Sajedi
Bin Lu
Xiyue Wang
Sadik Karma
Mitch Kostich
Sakthi Harini Rajendran
Dylan B Udy
Steven Chen
Alexander Arnuk
Abimbola Eunice Lawal
Kayla R Koenig
Meryl McKenna
Patrick K Reville
Hussein A Abbas
Omar Abdel-Wahab
Pedro Miura
Robert K Bradley
Eric Wang

Publication Date

9-3-2025

Journal

Blood Cancer Discovery

DOI

10.1158/2643-3230.BCD-24-0327

PMID

40632085

PMCID

PMC12405853

PubMedCentral® Posted Date

7-9-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Leukemia, Myeloid, Acute, Drug Resistance, Neoplasm, Core Binding Factor Alpha 2 Subunit, Tumor Suppressor Proteins, Protein Isoforms, Immediate-Early Proteins, Cell Line, Tumor, Gene Expression Regulation, Leukemic

Published Open-Access

yes

Recommended Citation

Han, Cuijuan; Zhang, Zhiping; Crosse, Edie I; et al., "An Isoform-Specific RUNX1C-BTG2 Axis Governs AML Quiescence and Chemoresistance" (2025). Faculty, Staff and Student Publications. 5228.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5228