Antineoplastic effects of pharmacological inhibitors of aurora kinases in CSF3RT618I-driven cells

by Selleckchem | Dec 14 2023

Myeloproliferative neoplasms (MPN) are consolidated as a relevant group of diseases derived from the malfunction of the hematopoiesis process and have as a particular attribute the increased proliferation of myeloid lineage. Among these, chronic neutrophilic leukemia (CNL) is distinguished, caused by the T618I mutation of the CSF3R gene, a trait that generates ligand-independent receptor activation and downstream JAK2/STAT signaling. Previous studies reported that mutations in BCR::ABL1 and JAK2V617F increased the expression of the aurora kinase A (AURKA) and B (AURKB) in Ba/F3 cells and their pharmacological inhibition displays antineoplastic effects in human BCR::ABL1 and JAK2V617F positive cells. Delimiting the current scenario, aspects related to the AURKA and AURKB as a potential target in CSF3RT618I-driven models is little known. In the present study, the cellular and molecular effects of pharmacological inhibitors of aurora kinases, such as aurora A inhibitor I, AZD1152-HQPA, and reversine, were evaluated in Ba/F3 expressing the CSF3RT618I mutation. AZD1152-HQPA and reversine demonstrated antineoplastic potential, causing a decrease in cell viability, clonogenicity, and proliferative capacity. At molecular levels, all inhibitors reduced histone H3 phosphorylation, aurora A inhibitor I and reversine reduced STAT5 phosphorylation, and AZD1152-HQPA and reversine induced PARP1 cleavage and γH2AX expression. Reversine more efficiently modulated genes associated with cell cycle and apoptosis compared to other drugs. In summary, our findings shed new insights into the use of AURKB inhibitors in the context of CNL.

Comments:

Your summary provides a comprehensive overview of the study's findings on the use of aurora kinase inhibitors in the context of chronic neutrophilic leukemia (CNL) driven by the CSF3RT618I mutation. Here's a breakdown of the key points from your description:

### Background:
- Myeloproliferative neoplasms (MPN) involve the increased proliferation of myeloid lineage cells.
- Chronic neutrophilic leukemia (CNL) is caused by the CSF3RT618I mutation in the CSF3R gene, leading to ligand-independent receptor activation and JAK2/STAT signaling.

### Previous Research:
- Mutations in BCR::ABL1 and JAK2V617F increase expression of aurora kinase A (AURKA) and B (AURKB).
- Inhibition of AURKA and AURKB has shown antineoplastic effects in BCR::ABL1 and JAK2V617F positive cells.

### Current Study:
- **Objective:** Evaluate the effects of aurora kinase inhibitors (aurora A inhibitor I, AZD1152-HQPA, and reversine) in Ba/F3 cells expressing the CSF3RT618I mutation.

### Findings:
- **Antineoplastic Effects:**
- AZD1152-HQPA and reversine reduced cell viability, clonogenicity, and proliferative capacity.

- **Molecular Effects:**
- All inhibitors reduced histone H3 phosphorylation.
- Aurora A inhibitor I and reversine reduced STAT5 phosphorylation.
- AZD1152-HQPA and reversine induced PARP1 cleavage and γH2AX expression.
- Reversine more efficiently modulated genes associated with cell cycle and apoptosis compared to other drugs.

### Conclusion:
- **Implications:** The study provides new insights into the potential use of AURKB inhibitors, particularly reversine, in the context of CNL driven by the CSF3RT618I mutation.

Your summary effectively captures the main outcomes of the research, outlining the impact of aurora kinase inhibitors on cellular and molecular levels in CNL.