# BCOR mutations define a therapeutic vulnerability to DHODH Inhibition in acute myeloid leukemia

## TL;DR

This study finds that AML cells with BCOR mutations are vulnerable to DHODH inhibitors, suggesting a new treatment strategy.

## Contribution

The study identifies a synthetic lethal interaction between BCOR mutations and DHODH inhibition in AML.

## Key findings

- BCOR-deficient cells are highly sensitive to DHODH inhibitors like brequinar and leflunomide.
- DHODH dependency in BCOR-mutant cells is linked to its role in the electron transport chain, not pyrimidine biosynthesis.

## Abstract

Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co-repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH’s role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.

The online version contains supplementary material available at 10.1007/s00277-026-06773-z.