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OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia

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 identi...

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Autores principales: Eisfelder, Bartholomew J., Saygin, Caner, Wynne, Joseph, Colton, Margaret W., Fischietti, Mariafausta, Beauchamp, Elspeth M., Cheng, Jason X., Odenike, Olatoyosi, Roboz, Gail, Alachkar, Houda, Stock, Wendy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930094/
https://www.ncbi.nlm.nih.gov/pubmed/33658483
http://dx.doi.org/10.1038/s41408-021-00433-3
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author Eisfelder, Bartholomew J.
Saygin, Caner
Wynne, Joseph
Colton, Margaret W.
Fischietti, Mariafausta
Beauchamp, Elspeth M.
Cheng, Jason X.
Odenike, Olatoyosi
Roboz, Gail
Alachkar, Houda
Stock, Wendy
author_facet Eisfelder, Bartholomew J.
Saygin, Caner
Wynne, Joseph
Colton, Margaret W.
Fischietti, Mariafausta
Beauchamp, Elspeth M.
Cheng, Jason X.
Odenike, Olatoyosi
Roboz, Gail
Alachkar, Houda
Stock, Wendy
author_sort Eisfelder, Bartholomew J.
collection PubMed
description 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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spelling pubmed-79300942021-03-19 OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia Eisfelder, Bartholomew J. Saygin, Caner Wynne, Joseph Colton, Margaret W. Fischietti, Mariafausta Beauchamp, Elspeth M. Cheng, Jason X. Odenike, Olatoyosi Roboz, Gail Alachkar, Houda Stock, Wendy Blood Cancer J Article 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. Nature Publishing Group UK 2021-03-03 /pmc/articles/PMC7930094/ /pubmed/33658483 http://dx.doi.org/10.1038/s41408-021-00433-3 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Eisfelder, Bartholomew J.
Saygin, Caner
Wynne, Joseph
Colton, Margaret W.
Fischietti, Mariafausta
Beauchamp, Elspeth M.
Cheng, Jason X.
Odenike, Olatoyosi
Roboz, Gail
Alachkar, Houda
Stock, Wendy
OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia
title OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia
title_full OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia
title_fullStr OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia
title_full_unstemmed OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia
title_short OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia
title_sort ots167 blocks flt3 translation and synergizes with flt3 inhibitors in flt3 mutant acute myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930094/
https://www.ncbi.nlm.nih.gov/pubmed/33658483
http://dx.doi.org/10.1038/s41408-021-00433-3
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