Cargando…

Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia

Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we...

Descripción completa

Detalles Bibliográficos
Autores principales: Alachkar, Houda, Mutonga, Martin B.G., Metzeler, Klaus H., Fulton, Noreen, Malnassy, Gregory, Herold, Tobias, Spiekermann, Karsten, Bohlander, Stefan K., Hiddemann, Wolfgang, Matsuo, Yo, Stock, Wendy, Nakamura, Yusuke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323011/
https://www.ncbi.nlm.nih.gov/pubmed/25365263
_version_ 1782356477525098496
author Alachkar, Houda
Mutonga, Martin B.G.
Metzeler, Klaus H.
Fulton, Noreen
Malnassy, Gregory
Herold, Tobias
Spiekermann, Karsten
Bohlander, Stefan K.
Hiddemann, Wolfgang
Matsuo, Yo
Stock, Wendy
Nakamura, Yusuke
author_facet Alachkar, Houda
Mutonga, Martin B.G.
Metzeler, Klaus H.
Fulton, Noreen
Malnassy, Gregory
Herold, Tobias
Spiekermann, Karsten
Bohlander, Stefan K.
Hiddemann, Wolfgang
Matsuo, Yo
Stock, Wendy
Nakamura, Yusuke
author_sort Alachkar, Houda
collection PubMed
description Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients.
format Online
Article
Text
id pubmed-4323011
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-43230112015-02-10 Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia Alachkar, Houda Mutonga, Martin B.G. Metzeler, Klaus H. Fulton, Noreen Malnassy, Gregory Herold, Tobias Spiekermann, Karsten Bohlander, Stefan K. Hiddemann, Wolfgang Matsuo, Yo Stock, Wendy Nakamura, Yusuke Oncotarget Research Paper Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients. Impact Journals LLC 2014-10-28 /pmc/articles/PMC4323011/ /pubmed/25365263 Text en Copyright: © 2014 Alachkar et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Alachkar, Houda
Mutonga, Martin B.G.
Metzeler, Klaus H.
Fulton, Noreen
Malnassy, Gregory
Herold, Tobias
Spiekermann, Karsten
Bohlander, Stefan K.
Hiddemann, Wolfgang
Matsuo, Yo
Stock, Wendy
Nakamura, Yusuke
Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia
title Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia
title_full Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia
title_fullStr Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia
title_full_unstemmed Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia
title_short Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia
title_sort preclinical efficacy of maternal embryonic leucine-zipper kinase (melk) inhibition in acute myeloid leukemia
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323011/
https://www.ncbi.nlm.nih.gov/pubmed/25365263
work_keys_str_mv AT alachkarhouda preclinicalefficacyofmaternalembryonicleucinezipperkinasemelkinhibitioninacutemyeloidleukemia
AT mutongamartinbg preclinicalefficacyofmaternalembryonicleucinezipperkinasemelkinhibitioninacutemyeloidleukemia
AT metzelerklaush preclinicalefficacyofmaternalembryonicleucinezipperkinasemelkinhibitioninacutemyeloidleukemia
AT fultonnoreen preclinicalefficacyofmaternalembryonicleucinezipperkinasemelkinhibitioninacutemyeloidleukemia
AT malnassygregory preclinicalefficacyofmaternalembryonicleucinezipperkinasemelkinhibitioninacutemyeloidleukemia
AT heroldtobias preclinicalefficacyofmaternalembryonicleucinezipperkinasemelkinhibitioninacutemyeloidleukemia
AT spiekermannkarsten preclinicalefficacyofmaternalembryonicleucinezipperkinasemelkinhibitioninacutemyeloidleukemia
AT bohlanderstefank preclinicalefficacyofmaternalembryonicleucinezipperkinasemelkinhibitioninacutemyeloidleukemia
AT hiddemannwolfgang preclinicalefficacyofmaternalembryonicleucinezipperkinasemelkinhibitioninacutemyeloidleukemia
AT matsuoyo preclinicalefficacyofmaternalembryonicleucinezipperkinasemelkinhibitioninacutemyeloidleukemia
AT stockwendy preclinicalefficacyofmaternalembryonicleucinezipperkinasemelkinhibitioninacutemyeloidleukemia
AT nakamurayusuke preclinicalefficacyofmaternalembryonicleucinezipperkinasemelkinhibitioninacutemyeloidleukemia