# Neddylation status determines the therapeutic sensitivity of tyrosine kinase inhibitors in chronic myeloid leukemia

## TL;DR

This study shows that the neddylation status affects how well tyrosine kinase inhibitors work in treating chronic myeloid leukemia.

## Contribution

The study reveals that neddylation agonists can enhance the effectiveness of tyrosine kinase inhibitors in CML.

## Key findings

- Neddylation inhibitors reduce the efficacy of tyrosine kinase inhibitors in CML cells and animal models.
- Neddylation agonists increase the sensitivity of CML cells to tyrosine kinase inhibitors.
- The ABL1 kinase domain is identified as a novel substrate for neddylation.

## Abstract

BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs) dominate the treatment of chronic myeloid leukemia (CML) over the past decades. In this study, we reported an unexpected role of neddylation inhibitors in desensitizing the therapeutic efficacy of BCR::ABL1-targeting TKIs in CML. Unlike their function in reducing drug resistance in many solid tumors, we revealed that neddylation inhibitors counteracted the cytotoxicity of TKIs against CML cells, both in cellular experiments and in animal model. Conversely, neddylation agonist sensitized the function of TKIs. RNA sequencing data revealed that neddylation inhibitor reversed the transcriptomic changes induced by TKI. Co-immunoprecipitation (co-IP) assay identified ABL1 kinase domain as a novel substrate for neddylation. Furthermore, an artificial intelligence (AI) 3-Dimensional spatial structure binding technology was employed to predict the impact of neddylation on the structure of ABL1 kinase domain. Finally, we provided potential evidence showing that TKI therapy decreased the expression of neddylation enzymes in the bone marrow of CML patients. Hence, our study offers new insights into the post-translational modification (PTM)-mediated drug resistance, and highlights the potential clinical benefits of neddylation agonists in improving the responsiveness of BCR::ABL1 TKIs in CML.

The online version contains supplementary material available at 10.1038/s41598-025-04153-7.