# Identification of an Ara-C resistance-related gene risk score and the role of S100A4 in AML via NR6A1-dependent activation and p53 regulation

## TL;DR

This study identifies a gene risk score for Ara-C resistance in AML and finds that S100A4 contributes to resistance through NR6A1 and p53 regulation.

## Contribution

The study introduces a novel gene risk score and reveals a new mechanism involving S100A4 in Ara-C resistance in AML.

## Key findings

- High ARRGRS is associated with worse prognosis and chemotherapy resistance in AML patients.
- S100A4 promotes Ara-C resistance by upregulating p53 via NR6A1-dependent activation.
- Targeting S100A4 may help overcome chemotherapy resistance in AML.

## Abstract

Ara‐C (cytarabine) resistance remains a significant contributor to the poor clinical outcomes in adult acute myeloid leukemia (AML). However, predicting Ara‐C resistance and developing effective targeted therapies remain challenging.

In this study, we integrated transcriptional data from Ara‐C‐resistant cell lines in the GEO database and the TCGA‐LAML cohort to establish an Ara‐C resistancerelated gene risk score (ARRGRS). Kaplan‐Meier survival analysis revealed that AML patients with high ARRGRS had significantly worse prognosis compared to those with low ARRGRS in both cohorts. Additionally, ARRGRS effectively predicted chemotherapy response in AML patients across both cohorts. To further elucidate the mechanisms underlying Ara‐C resistance, we constructed Ara‐C‐resistant AML cell lines and validated our findings using qPCR, Western blotting, flow cytometry (FCM), and in vivo experiments.

We discovered that high expression of S100A4 promotes Ara‐C resistance in AML. Mechanistically, we identified that the transcription factor NR6A1 directly binds to the S100A4 promoter, enhancing its transcriptional activity. Subsequently, S100A4 upregulates p53 expression, thereby promoting AML cell proliferation and resistance to Ara‐C.

In summary, our comprehensive investigation of the ARRGRS not only deepens the understanding of Ara‐C resistance mechanisms but also provides promising insights for targeting S100A4 to inhibit tumor growth and overcome chemotherapy resistance in AML.