ArticleBlood cancer journal2021
OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia.
Article in Blood cancer journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 12 citations in OpenAlex.
- Targeting Menin in T-lineage Acute Lymphoblastic Leukemia.Molecular cancer therapeutics · 2026Article
- Targeting MELK in tumor cells and tumor microenvironment: from function and mechanism to therapeutic application.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025Review
- Melk facilitates pulmonary artery smooth muscle cell proliferation and migration in pulmonary hypertension via modulation of YAP/TAZ signaling.Frontiers in cell and developmental biology · 2025Article
- The Dual PIM/FLT3 Inhibitor MEN1703 Combines Synergistically With Gilteritinib in FLT3-ITD-Mutant Acute Myeloid Leukaemia.Journal of cellular and molecular medicine · 2024Article
- Discovery of first-in-class PROTACs targeting maternal embryonic leucine zipper kinase (MELK) for the treatment of Burkitt lymphoma.RSC medicinal chemistry · 2024Article
- Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Strategies targeting FLT3 beyond the kinase inhibitors.Pharmacology & therapeutics · 2021Review
- Deficiency of eIF4B Increases Mouse Mortality and Impairs Antiviral Immunity.Frontiers in immunology · 2021Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Internal tandem duplication (-ITD) mutations of Fms-like tyrosine kinase 3 (FLT3) provide growth and pro-survival signals in the context of established driver mutations in FLT3 mutant acute myeloid leukemia (AML). Maternal embryonic leucine zipper kinase (MELK) is an aberrantly expressed gene identified as a target in AML. The MELK inhibitor OTS167 induces cell death in AML including cells with FLT3 mutations, yet the role of MELK and mechanisms of OTS167 function are not understood. OTS167 alone or in combination with tyrosine kinase inhibitors (TKIs) were used to investigate the effect of OTS167 on FLT3 signaling and expression in human FLT3 mutant AML cell lines and primary cells. We describe a mechanism whereby OTS167 blocks FLT3 expression by blocking FLT3 translation and inhibiting phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and eukaryotic translation initiation factor 4B (eIF4B). OTS167 in combination with TKIs results in synergistic induction of FLT3 mutant cell death in FLT3 mutant cell lines and prolonged survival in a FLT3 mutant AML xenograft mouse model. Our findings suggest signaling through MELK is necessary for the translation and expression of FLT3-ITD, and blocking MELK with OTS167 represents a viable therapeutic strategy for patients with FLT3 mutant AML.
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