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Combination Therapies Targeting Apoptosis in Paediatric AML: Understanding the Molecular Mechanisms of AML Treatments Using Phosphoproteomics

Paediatric acute myeloid leukaemia (AML) continues to present treatment challenges, as no “standard approach” exists to treat those young patients reliably and safely. Combination therapies could become a viable treatment option for treating young patients with AML, allowing multiple pathways to be...

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Detalles Bibliográficos
Autores principales: Ali, Ahlam A., Cairns, Lauren V., Clarke, Kathryn M., Blayney, Jaine K., Lappin, Katrina M., Mills, Ken I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10058112/
https://www.ncbi.nlm.nih.gov/pubmed/36982791
http://dx.doi.org/10.3390/ijms24065717
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author Ali, Ahlam A.
Cairns, Lauren V.
Clarke, Kathryn M.
Blayney, Jaine K.
Lappin, Katrina M.
Mills, Ken I.
author_facet Ali, Ahlam A.
Cairns, Lauren V.
Clarke, Kathryn M.
Blayney, Jaine K.
Lappin, Katrina M.
Mills, Ken I.
author_sort Ali, Ahlam A.
collection PubMed
description Paediatric acute myeloid leukaemia (AML) continues to present treatment challenges, as no “standard approach” exists to treat those young patients reliably and safely. Combination therapies could become a viable treatment option for treating young patients with AML, allowing multiple pathways to be targeted. Our in silico analysis of AML patients highlighted “cell death and survival” as an aberrant, potentially targetable pathway in paediatric AML patients. Therefore, we aimed to identify novel combination therapies to target apoptosis. Our apoptotic drug screening resulted in the identification of one potential “novel” drug pairing, comprising the Bcl-2 inhibitor ABT-737 combined with the CDK inhibitor Purvalanol-A, as well as one triple combination of ABT-737 + AKT inhibitor + SU9516, which showed significant synergism in a series of paediatric AML cell lines. Using a phosphoproteomic approach to understand the apoptotic mechanism involved, proteins related to apoptotic cell death and cell survival were represented, in agreement with further results showing differentially expressed apoptotic proteins and their phosphorylated forms among combination treatments compared to single-agent treated cells such upregulation of BAX and its phosphorylated form (Thr167), dephosphorylation of BAD (Ser 112), and downregulation of MCL-1 and its phosphorylated form (Ser159/Thr 163). Total levels of Bcl-2 were decreased but correlated with increased levels of phosphorylated Bcl-2, which was consistent with our phosphoproteomic analysis predictions. Bcl-2 phosphorylation was regulated by extracellular-signal-regulated kinase (ERK) but not PP2A phosphatase. Although the mechanism linking to Bcl-2 phosphorylation remains to be determined, our findings provide first-hand insights on potential novel combination treatments for AML.
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spelling pubmed-100581122023-03-30 Combination Therapies Targeting Apoptosis in Paediatric AML: Understanding the Molecular Mechanisms of AML Treatments Using Phosphoproteomics Ali, Ahlam A. Cairns, Lauren V. Clarke, Kathryn M. Blayney, Jaine K. Lappin, Katrina M. Mills, Ken I. Int J Mol Sci Article Paediatric acute myeloid leukaemia (AML) continues to present treatment challenges, as no “standard approach” exists to treat those young patients reliably and safely. Combination therapies could become a viable treatment option for treating young patients with AML, allowing multiple pathways to be targeted. Our in silico analysis of AML patients highlighted “cell death and survival” as an aberrant, potentially targetable pathway in paediatric AML patients. Therefore, we aimed to identify novel combination therapies to target apoptosis. Our apoptotic drug screening resulted in the identification of one potential “novel” drug pairing, comprising the Bcl-2 inhibitor ABT-737 combined with the CDK inhibitor Purvalanol-A, as well as one triple combination of ABT-737 + AKT inhibitor + SU9516, which showed significant synergism in a series of paediatric AML cell lines. Using a phosphoproteomic approach to understand the apoptotic mechanism involved, proteins related to apoptotic cell death and cell survival were represented, in agreement with further results showing differentially expressed apoptotic proteins and their phosphorylated forms among combination treatments compared to single-agent treated cells such upregulation of BAX and its phosphorylated form (Thr167), dephosphorylation of BAD (Ser 112), and downregulation of MCL-1 and its phosphorylated form (Ser159/Thr 163). Total levels of Bcl-2 were decreased but correlated with increased levels of phosphorylated Bcl-2, which was consistent with our phosphoproteomic analysis predictions. Bcl-2 phosphorylation was regulated by extracellular-signal-regulated kinase (ERK) but not PP2A phosphatase. Although the mechanism linking to Bcl-2 phosphorylation remains to be determined, our findings provide first-hand insights on potential novel combination treatments for AML. MDPI 2023-03-16 /pmc/articles/PMC10058112/ /pubmed/36982791 http://dx.doi.org/10.3390/ijms24065717 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ali, Ahlam A.
Cairns, Lauren V.
Clarke, Kathryn M.
Blayney, Jaine K.
Lappin, Katrina M.
Mills, Ken I.
Combination Therapies Targeting Apoptosis in Paediatric AML: Understanding the Molecular Mechanisms of AML Treatments Using Phosphoproteomics
title Combination Therapies Targeting Apoptosis in Paediatric AML: Understanding the Molecular Mechanisms of AML Treatments Using Phosphoproteomics
title_full Combination Therapies Targeting Apoptosis in Paediatric AML: Understanding the Molecular Mechanisms of AML Treatments Using Phosphoproteomics
title_fullStr Combination Therapies Targeting Apoptosis in Paediatric AML: Understanding the Molecular Mechanisms of AML Treatments Using Phosphoproteomics
title_full_unstemmed Combination Therapies Targeting Apoptosis in Paediatric AML: Understanding the Molecular Mechanisms of AML Treatments Using Phosphoproteomics
title_short Combination Therapies Targeting Apoptosis in Paediatric AML: Understanding the Molecular Mechanisms of AML Treatments Using Phosphoproteomics
title_sort combination therapies targeting apoptosis in paediatric aml: understanding the molecular mechanisms of aml treatments using phosphoproteomics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10058112/
https://www.ncbi.nlm.nih.gov/pubmed/36982791
http://dx.doi.org/10.3390/ijms24065717
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