Document Type
Article
Publication Date
9-3-2025
Original Citation
Han C,
Zhang Z,
Crosse E,
Sajedi S,
Lu B,
Wang X,
Karma S,
Kostich MS,
Rajendran S,
Udy D,
Chen S,
Arnuk A,
Lawal A,
Koenig K,
McKenna M,
Reville P,
Abbas H,
Abdel-Wahab O,
Miura P,
Bradley R,
Wang E.
An Isoform-Specific RUNX1C-BTG2 Axis Governs AML Quiescence and Chemoresistance. Blood Cancer Discov. 2025;6(5):464-83.
Keywords
JGM, SS1, 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
JAX Source
Blood Cancer Discov. 2025;6(5):464-83.
ISSN
2643-3249
PMID
40632085
DOI
https://doi.org/10.1158/2643-3230.BCD-24-0327
Grant
E. Wang was supported by JAX Cancer Center New Investigator Award (P30CA034196), JAX start-up funds, JAX Cancer Center Fast Forward Award, the Leukemia Research Foundation, and the Butler Family Foundation.
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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