HOX Codes and RUNX1T1: Unveiling Lineage Plasticity in Cancer
Publication Title: HOX code–based stratification reveals RUNX1T1–HDAC reprogramming as a targetable driver of lineage plasticity across cancers
Summary
- Question
- This study explored the role of Homeobox (HOX) gene expression patterns, known as the HOX code, in identifying and understanding cancer lineage plasticity. Lineage plasticity refers to the ability of cancer cells to change their identity, enabling them to evade therapies and develop resistance. The researchers investigated how HOX codes might serve as universal markers of lineage plasticity across multiple cancer types and identified the RUNX1T1 protein as a key driver of this process.
- Why it Matters
- Cancer lineage plasticity is a significant challenge in treating aggressive cancers, such as prostate, lung, and acute myeloid leukemia (AML), as it often leads to therapy resistance and tumor progression. Understanding and identifying plasticity at a molecular level can improve the ability to predict treatment resistance and develop targeted therapies. This research not only highlights the HOX code as a potential biomarker for detecting plasticity but also identifies the RUNX1T1 protein as a targetable driver, offering new therapeutic opportunities for managing resistant cancers.
- Methods
- The researchers analyzed RNA sequencing data from over 80,000 samples across 23 cancer types to evaluate the expression of 39 HOX genes. They compared lineage-constrained (stable) and lineage-plastic (identity-changing) cancer subtypes, focusing on prostate cancer, lung cancer, and AML. Functional experiments, including genetic manipulation and pharmacologic inhibition, were conducted to validate the role of RUNX1T1 in plasticity.
- Key Findings
- HOX codes effectively distinguished lineage-constrained from lineage-plastic cancers across various types. RUNX1T1, a protein associated with the HOX code, was consistently upregulated in plastic cancers. RUNX1T1 was shown to repress differentiation programs by remodeling the epigenetic landscape, specifically by recruiting a complex of proteins (NCOR/HDAC3) that silences genes critical for maintaining stable cancer cell identities. Targeting RUNX1T1 or HDAC3 with drugs or genetic silencing suppressed the growth of lineage-plastic cancer cells.
- Implications
- These findings establish HOX codes as a universal framework for identifying cancer lineage plasticity, which could be used to predict therapy resistance. RUNX1T1 represents a promising therapeutic target, as its inhibition selectively impairs plastic, treatment-resistant cancer cells while sparing stable cells. This research paves the way for developing targeted treatments aimed at overcoming resistance mechanisms in aggressive cancers.
- Next Steps
- Future research should explore the clinical application of HOX code analysis as a biomarker for therapy resistance. Additional studies are needed to evaluate the efficacy of RUNX1T1 and HDAC3 inhibitors in preclinical and clinical settings. Expanding the investigation to other cancer types may further validate the universality of the HOX code and RUNX1T1's role in lineage plasticity.
- Funding Information
- This research was supported by the National Cancer Institute/National Institutes of Health (awards R00CA218885, R37CA258730, R01CA288820, R01CA292949, and P30CA016359). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional funding was provided by the Department of Defense (awards W81XWH-18-1-0411 and W81XWH21-1-0520), the Cancer Prevention Research Institute of Texas (awards RR170050 and RP220473), the Prostate Cancer Foundation (awards 25CHAL05 and 17YOUN12), and the Yale Cancer Center CCSG Pilot Grant.
Full Citation
Jiang Y, Cheng S, Zhang CY, Jin X, Li L, Shin HE, Alrefai A, Luo A, Xu Y, Kim IY, Mu P. HOX code–based stratification reveals RUNX1T1–HDAC reprogramming as a targetable driver of lineage plasticity across cancers. Cancer Letters 2026, 648: 218465. DOI: 10.1016/j.canlet.2026.218465.