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

Formaldehyde is a colorless, strong-smelling chemical widely used in industrial and household products, including building materials and furniture manufacturing. Chronic exposure, even at low doses, has been associated with respiratory disease, neurotoxicity, immune dysregulation, and cancer. Although growing epidemiological evidence suggests a link between formaldehyde exposure and increased leukemia risk, the underlying molecular mechanisms remain poorly defined due to its high reactivity and limited biological traceability. In this study, we show that low-dose formaldehyde exposure (3 ppm) upregulates key oncogenic regulators-including RUNX1, ETV6, OCT4, and ISX-in B-ALL cell lines. Transcriptomic profiling combined with functional assays reveals that formaldehyde activates a RUNX1-ISX signaling axis, which in turn drives the expression of downstream oncogenic transcription factors (YBX2, HES2, FOXH1, MYCL, FOS, and PBX4). This activation reshapes transcriptional programs across major cancer-associated pathways, including metabolic signaling and hematopoietic cell-lineage regulation, ultimately promoting malignant activity and tumor formation in a xenograft model. Importantly, pharmacologic inhibition of the RUNX1-ISX axis significantly attenuated formaldehyde-induced oncogenic effects and reduced tumor growth. Analysis of human samples using immunofluorescence and Pearson correlation further confirmed a strong co-expression relationship between RUNX1 and ISX. Collectively, these findings identify the RUNX1-ISX axis as a critical mediator of formaldehyde-induced oncogenesis in B-ALL and highlight it as a promising therapeutic target for mitigating environmental leukemogenic risk.