Cargando…

Peptide microarray profiling identifies phospholipase C gamma 1 (PLC-γ1) as a potential target for t(8;21) AML

The t(8;21) (q22;q22) chromosomal translocation is one of the most frequent genetic alterations in acute myeloid leukemia (AML) which has a need for improved therapeutic strategies. We found PLC-γ1 as one of the highest phosphorylated peptides in t(8;21) AML samples compared to NBM or CN-AML in our...

Descripción completa

Detalles Bibliográficos
Autores principales: Mahmud, Hasan, Scherpen, Frank J.G., de Boer, Tiny Meeuwsen, Lourens, Harm-Jan, Schoenherr, Caroline, Eder, Matthias, Scherr, Michaela, Guryev, Victor, De Bont, Eveline S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620177/
https://www.ncbi.nlm.nih.gov/pubmed/28978037
http://dx.doi.org/10.18632/oncotarget.18631
_version_ 1783267529766993920
author Mahmud, Hasan
Scherpen, Frank J.G.
de Boer, Tiny Meeuwsen
Lourens, Harm-Jan
Schoenherr, Caroline
Eder, Matthias
Scherr, Michaela
Guryev, Victor
De Bont, Eveline S.
author_facet Mahmud, Hasan
Scherpen, Frank J.G.
de Boer, Tiny Meeuwsen
Lourens, Harm-Jan
Schoenherr, Caroline
Eder, Matthias
Scherr, Michaela
Guryev, Victor
De Bont, Eveline S.
author_sort Mahmud, Hasan
collection PubMed
description The t(8;21) (q22;q22) chromosomal translocation is one of the most frequent genetic alterations in acute myeloid leukemia (AML) which has a need for improved therapeutic strategies. We found PLC-γ1 as one of the highest phosphorylated peptides in t(8;21) AML samples compared to NBM or CN-AML in our previous peptide microarray. PLC-γ1 is known to play a role in cancer progression, however, the impact of PLC-γ1 in AML is currently unknown. Therefore, we aimed to study the functional role of PLC-γ1 by investigating the cellular growth, survival and its underlying mechanism in t(8;21) AML. In this study, PLC-γ1 expression was significantly higher in t(8;21) AML compared to other karyotypes. The PLC-γ1 protein expression was suppressed in AML1-ETO knock down cells indicating that it might induce kasumi-1 cell death. ShRNA-mediated PLC-γ1 knockdown in kasumi-1 cells significantly blocked cell growth, induced apoptosis and cell cycle arrest which was explained by the increased activation of apoptotic related and cell cycle regulatory protein expressions. Gene expression array analysis showed the up-regulation of apoptotic and DNA damage response genes together with the downregulation of cell growth, proliferation and differentiation genes in the PLC-γ1 suppressed kasumi-1 cells, consistent with the observed phenotypic effects. Importantly, PLC-γ1 suppressed kasumi-1 cells showed higher chemosensitivity to the chemotherapeutic drug treatments and lower cell proliferation upon hypoxic stress. Taken together, these in vitro finding strongly support an important role for PLC-γ1 in the survival of t(8;21) AML mimicking kasumi-1 cells and identify PLC-γ1 as a potential therapeutic target for t(8;21) AML treatment.
format Online
Article
Text
id pubmed-5620177
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-56201772017-10-03 Peptide microarray profiling identifies phospholipase C gamma 1 (PLC-γ1) as a potential target for t(8;21) AML Mahmud, Hasan Scherpen, Frank J.G. de Boer, Tiny Meeuwsen Lourens, Harm-Jan Schoenherr, Caroline Eder, Matthias Scherr, Michaela Guryev, Victor De Bont, Eveline S. Oncotarget Research Paper The t(8;21) (q22;q22) chromosomal translocation is one of the most frequent genetic alterations in acute myeloid leukemia (AML) which has a need for improved therapeutic strategies. We found PLC-γ1 as one of the highest phosphorylated peptides in t(8;21) AML samples compared to NBM or CN-AML in our previous peptide microarray. PLC-γ1 is known to play a role in cancer progression, however, the impact of PLC-γ1 in AML is currently unknown. Therefore, we aimed to study the functional role of PLC-γ1 by investigating the cellular growth, survival and its underlying mechanism in t(8;21) AML. In this study, PLC-γ1 expression was significantly higher in t(8;21) AML compared to other karyotypes. The PLC-γ1 protein expression was suppressed in AML1-ETO knock down cells indicating that it might induce kasumi-1 cell death. ShRNA-mediated PLC-γ1 knockdown in kasumi-1 cells significantly blocked cell growth, induced apoptosis and cell cycle arrest which was explained by the increased activation of apoptotic related and cell cycle regulatory protein expressions. Gene expression array analysis showed the up-regulation of apoptotic and DNA damage response genes together with the downregulation of cell growth, proliferation and differentiation genes in the PLC-γ1 suppressed kasumi-1 cells, consistent with the observed phenotypic effects. Importantly, PLC-γ1 suppressed kasumi-1 cells showed higher chemosensitivity to the chemotherapeutic drug treatments and lower cell proliferation upon hypoxic stress. Taken together, these in vitro finding strongly support an important role for PLC-γ1 in the survival of t(8;21) AML mimicking kasumi-1 cells and identify PLC-γ1 as a potential therapeutic target for t(8;21) AML treatment. Impact Journals LLC 2017-06-27 /pmc/articles/PMC5620177/ /pubmed/28978037 http://dx.doi.org/10.18632/oncotarget.18631 Text en Copyright: © 2017 Mahmud et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Mahmud, Hasan
Scherpen, Frank J.G.
de Boer, Tiny Meeuwsen
Lourens, Harm-Jan
Schoenherr, Caroline
Eder, Matthias
Scherr, Michaela
Guryev, Victor
De Bont, Eveline S.
Peptide microarray profiling identifies phospholipase C gamma 1 (PLC-γ1) as a potential target for t(8;21) AML
title Peptide microarray profiling identifies phospholipase C gamma 1 (PLC-γ1) as a potential target for t(8;21) AML
title_full Peptide microarray profiling identifies phospholipase C gamma 1 (PLC-γ1) as a potential target for t(8;21) AML
title_fullStr Peptide microarray profiling identifies phospholipase C gamma 1 (PLC-γ1) as a potential target for t(8;21) AML
title_full_unstemmed Peptide microarray profiling identifies phospholipase C gamma 1 (PLC-γ1) as a potential target for t(8;21) AML
title_short Peptide microarray profiling identifies phospholipase C gamma 1 (PLC-γ1) as a potential target for t(8;21) AML
title_sort peptide microarray profiling identifies phospholipase c gamma 1 (plc-γ1) as a potential target for t(8;21) aml
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620177/
https://www.ncbi.nlm.nih.gov/pubmed/28978037
http://dx.doi.org/10.18632/oncotarget.18631
work_keys_str_mv AT mahmudhasan peptidemicroarrayprofilingidentifiesphospholipasecgamma1plcg1asapotentialtargetfort821aml
AT scherpenfrankjg peptidemicroarrayprofilingidentifiesphospholipasecgamma1plcg1asapotentialtargetfort821aml
AT deboertinymeeuwsen peptidemicroarrayprofilingidentifiesphospholipasecgamma1plcg1asapotentialtargetfort821aml
AT lourensharmjan peptidemicroarrayprofilingidentifiesphospholipasecgamma1plcg1asapotentialtargetfort821aml
AT schoenherrcaroline peptidemicroarrayprofilingidentifiesphospholipasecgamma1plcg1asapotentialtargetfort821aml
AT edermatthias peptidemicroarrayprofilingidentifiesphospholipasecgamma1plcg1asapotentialtargetfort821aml
AT scherrmichaela peptidemicroarrayprofilingidentifiesphospholipasecgamma1plcg1asapotentialtargetfort821aml
AT guryevvictor peptidemicroarrayprofilingidentifiesphospholipasecgamma1plcg1asapotentialtargetfort821aml
AT debontevelines peptidemicroarrayprofilingidentifiesphospholipasecgamma1plcg1asapotentialtargetfort821aml