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HOX code-based stratification reveals RUNX1T1-HDAC reprogramming as a targetable driver of lineage plasticity across

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Summary

Homeobox (HOX) gene expression patterns identify cancer lineage plasticity across multiple cancer types. This study reveals RUNX1T1 as a key regulator of this plasticity, offering a new therapeutic target for cancer treatment.

Keywords:
AMLArtificial intelligenceHDACHOX codeLineage plasticityLung cancerNanoparticleProstate cancerRUNX1T1

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Lineage plasticity is a key driver of cancer therapy resistance and progression.
  • Current methods for identifying plastic cancer subtypes lack scalability and cross-cancer applicability.
  • Homeobox (HOX) genes establish cell identity through specific expression patterns (HOX codes).

Purpose of the Study:

  • To identify cross-cancer markers for lineage plasticity.
  • To investigate the role of HOX gene expression in stratifying cancer subtypes.
  • To uncover novel therapeutic targets for lineage-plastic cancers.

Main Methods:

  • Analysis of multi-omics data from over 80,000 RNA-seq samples across 23 cancer types.
  • Differential expression analysis to identify key regulators.
  • AI-based structural modeling, co-immunoprecipitation, and CUT&RUN profiling.
  • Functional validation in preclinical cancer models and testing of therapeutic interventions.

Main Results:

  • HOX code expression robustly stratifies lineage-constrained and lineage-plastic cancer states across multiple cancer types.
  • Previously unrecognized plastic subtypes were identified in prostate cancer, lung cancer, and acute myeloid leukemia (AML).
  • RUNX1T1 was identified as a consistent regulator of HOX-defined plasticity, interacting with the NCOR/HDAC3 complex to remodel chromatin.
  • Inhibition of HDAC3 or RUNX1T1 suppressed the growth of lineage-plastic cancer cells.

Conclusions:

  • HOX code expression serves as a scalable marker for cancer lineage plasticity.
  • RUNX1T1 is a cross-lineage regulator of HOX code-defined plasticity.
  • The RUNX1T1-HDAC axis represents a therapeutically actionable vulnerability in lineage-plastic cancers.