Formaldehyde activates the RUNX1-ISX axis to promote leukemic reprogramming, a pathway associated with poor prognosis...

Area of Science:

• Environmental Health
• Molecular Oncology
• Toxicology

Background:

• Formaldehyde is a ubiquitous chemical linked to cancer, particularly leukemia.
• Molecular mechanisms of formaldehyde-induced leukemia are poorly understood due to its reactivity.
• Epidemiological studies suggest a correlation between formaldehyde exposure and increased leukemia risk.

Purpose of the Study:

• To elucidate the molecular pathways mediating formaldehyde-induced oncogenesis in B-cell acute lymphoblastic leukemia (B-ALL).
• To identify potential therapeutic targets for mitigating formaldehyde-related leukemia risk.

Main Methods:

• Utilized B-ALL cell lines and a xenograft mouse model.
• Administered low-dose formaldehyde exposure (3 ppm).
• Performed transcriptomic profiling, functional assays, pharmacologic inhibition, immunofluorescence, and Pearson correlation analysis.

Main Results:

• Low-dose formaldehyde upregulates oncogenic regulators RUNX1, ETV6, OCT4, and ISX in B-ALL cells.
• Formaldehyde activates a RUNX1-ISX signaling axis, driving downstream oncogenic transcription factors and reshaping cancer-associated pathways.
• Pharmacologic inhibition of the RUNX1-ISX axis attenuated formaldehyde-induced oncogenic effects and reduced tumor growth.
• Human samples showed a strong co-expression of RUNX1 and ISX.

Conclusions:

• The RUNX1-ISX axis is a critical mediator of formaldehyde-induced oncogenesis in B-ALL.
• Targeting the RUNX1-ISX axis offers a promising therapeutic strategy for formaldehyde-related leukemia.
• This study provides novel insights into the molecular basis of environmental leukemogenesis.