The FLT3 internal tandem duplication mutation is a secondary target of the aurora B kinase inhibitor AZD1152-HQPA in acute myelogenous leukemia cells

Grundy, Martin; Seedhouse, Claire; Shang, Shilli; Richardson, Jaineeta; Russell, Nigel; Pallis, Monica

Abstract

Aurora kinases play an essential role in orchestrating chromosome alignment, segregation, and cytokinesis during mitotic progression and both aurora-A and B are frequently overexpressed in a variety of human malignancies. In this study, we report the effects of AZD1152-HQPA, a highly selective inhibitor of aurora-B kinase, in acute myeloid leukemia (AML) cell lines and primary samples. We show that AZD1152-HQPA inhibits the phosphorylation of Histone H3 (pHH3) on serine 10 resulting in polyploid cells, apoptosis, and loss of viability in a panel of AML cell lines.We also show that AZD1152-HQPA sensitivity in our cell lines is irrespective of p53 status and the FLT3-ITD–expressing MOLM-13 and MV4-11 cell lines are particularly sensitive to AZD1152-HQPA. Internal tandem duplications (ITD) within the FLT3 tyrosine kinase receptor are found in ∼25% of AML patients and are associated with a poor prognosis. Here, we report that AZD1152-HQPA directly targets phosphorylated FLT3 along with inhibiting its downstream target phospho–signal transducer and activator of transcription 5 (STAT5) in the FLT3-ITD cell lines.We show pHH3 expression in primary AML blasts and its inhibition by AZD1152-HQPA at low doses in all of our primary samples tested. AZD1152-HQPA inhibits the clonogenic potential of primary AML samples, with FLT3-ITD samples being the most sensitive (P = 0.029). FLT3-ITD primary samples are also more sensitive to pHH3 inhibition (P = 0.022) and are particularly sensitive to pSTAT5 downregulation after treatment with AZD1152-HQPAcompared with FLT3 wild-type samples (P = 0.007). We conclude that mutant FLT3 is a secondary target of AZD1152-HQPA and that FLT3- ITD primary samples are particularly sensitive to the drug.

Citation

Grundy, M., Seedhouse, C., Shang, S., Richardson, J., Russell, N., & Pallis, M. (2010). The FLT3 internal tandem duplication mutation is a secondary target of the aurora B kinase inhibitor AZD1152-HQPA in acute myelogenous leukemia cells. Molecular Cancer Therapeutics, 9(3), https://doi.org/10.1158/1535-7163.MCT-09-1144

• Journal Article Type: Article
• Publication Date: 2010
• Deposit Date: Apr 5, 2024
• Journal: Molecular Cancer Therapeutics
• Print ISSN: 1535-7163
• Electronic ISSN: 1538-8514
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 3
• DOI: https://doi.org/10.1158/1535-7163.MCT-09-1144
• Public URL: https://nottingham-repository.worktribe.com/output/32755038
• Publisher URL: https://aacrjournals.org/mct/article/9/3/661/93678/The-FLT3-Internal-Tandem-Duplication-Mutation-Is-a