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New Drug Repositioning Candidates for T-ALL Identified Via Human/Murine Gene Signature Comparison

T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive subtype of leukemia for which important progress in treatment efficiency have been made in the past decades to reach a cure rate of 75%–80% nowadays. It is nevertheless mandatory to find new targets and active molecules for innovative ther...

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Autores principales: Bonnet, Raphaël, Nebout, Marielle, Brousse, Carine, Reinier, Frédéric, Imbert, Véronique, Rohrlich, Pierre Simon, Peyron, Jean-François
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680901/
https://www.ncbi.nlm.nih.gov/pubmed/33240808
http://dx.doi.org/10.3389/fonc.2020.557643
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author Bonnet, Raphaël
Nebout, Marielle
Brousse, Carine
Reinier, Frédéric
Imbert, Véronique
Rohrlich, Pierre Simon
Peyron, Jean-François
author_facet Bonnet, Raphaël
Nebout, Marielle
Brousse, Carine
Reinier, Frédéric
Imbert, Véronique
Rohrlich, Pierre Simon
Peyron, Jean-François
author_sort Bonnet, Raphaël
collection PubMed
description T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive subtype of leukemia for which important progress in treatment efficiency have been made in the past decades to reach a cure rate of 75%–80% nowadays. It is nevertheless mandatory to find new targets and active molecules for innovative therapeutic strategies as relapse is associated with a very dismal outcome. We designed an experimental workflow to highlight the conserved core pathways associated with leukemogenesis by confronting the gene expression profiles (GEPs) of human T-ALL cases to the GEP of a murine T-ALL representative model, generated by the conditional deletion of the PTEN tumor suppressor gene in T cell precursors (tPTEN-/-). We identified 844 differentially expressed genes, common GEPs (cGEP) that were conserved between human T-ALL and murine signatures, and also similarly differentially expressed, compared to normal T cells. Using bioinformatic tools we highlighted in cGEPan upregulation of E2F, MYC and mTORC1. Next, using Connectivity Map (CMAP) and CMAPViz a visualization procedure for CMAP data that we developed, we selected in silico three FDA-approved, bioactive molecule candidates: α-estradiol (α-E), nordihydroguaiaretic acid (NDGA) and prochlorperazine dimaleate (PCZ). At a biological level, we showed that the three drugs triggered an apoptotic cell death in a panel of T-ALL cell lines, activated a DNA damage response and interfered with constitutive mTORC1 activation and c-MYC expression. This analysis shows that the investigation of conserved leukemogenesis pathways could be a strategy to reveal new avenues for pharmacological intervention.
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spelling pubmed-76809012020-11-24 New Drug Repositioning Candidates for T-ALL Identified Via Human/Murine Gene Signature Comparison Bonnet, Raphaël Nebout, Marielle Brousse, Carine Reinier, Frédéric Imbert, Véronique Rohrlich, Pierre Simon Peyron, Jean-François Front Oncol Oncology T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive subtype of leukemia for which important progress in treatment efficiency have been made in the past decades to reach a cure rate of 75%–80% nowadays. It is nevertheless mandatory to find new targets and active molecules for innovative therapeutic strategies as relapse is associated with a very dismal outcome. We designed an experimental workflow to highlight the conserved core pathways associated with leukemogenesis by confronting the gene expression profiles (GEPs) of human T-ALL cases to the GEP of a murine T-ALL representative model, generated by the conditional deletion of the PTEN tumor suppressor gene in T cell precursors (tPTEN-/-). We identified 844 differentially expressed genes, common GEPs (cGEP) that were conserved between human T-ALL and murine signatures, and also similarly differentially expressed, compared to normal T cells. Using bioinformatic tools we highlighted in cGEPan upregulation of E2F, MYC and mTORC1. Next, using Connectivity Map (CMAP) and CMAPViz a visualization procedure for CMAP data that we developed, we selected in silico three FDA-approved, bioactive molecule candidates: α-estradiol (α-E), nordihydroguaiaretic acid (NDGA) and prochlorperazine dimaleate (PCZ). At a biological level, we showed that the three drugs triggered an apoptotic cell death in a panel of T-ALL cell lines, activated a DNA damage response and interfered with constitutive mTORC1 activation and c-MYC expression. This analysis shows that the investigation of conserved leukemogenesis pathways could be a strategy to reveal new avenues for pharmacological intervention. Frontiers Media S.A. 2020-11-09 /pmc/articles/PMC7680901/ /pubmed/33240808 http://dx.doi.org/10.3389/fonc.2020.557643 Text en Copyright © 2020 Bonnet, Nebout, Brousse, Reinier, Imbert, Rohrlich and Peyron http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Bonnet, Raphaël
Nebout, Marielle
Brousse, Carine
Reinier, Frédéric
Imbert, Véronique
Rohrlich, Pierre Simon
Peyron, Jean-François
New Drug Repositioning Candidates for T-ALL Identified Via Human/Murine Gene Signature Comparison
title New Drug Repositioning Candidates for T-ALL Identified Via Human/Murine Gene Signature Comparison
title_full New Drug Repositioning Candidates for T-ALL Identified Via Human/Murine Gene Signature Comparison
title_fullStr New Drug Repositioning Candidates for T-ALL Identified Via Human/Murine Gene Signature Comparison
title_full_unstemmed New Drug Repositioning Candidates for T-ALL Identified Via Human/Murine Gene Signature Comparison
title_short New Drug Repositioning Candidates for T-ALL Identified Via Human/Murine Gene Signature Comparison
title_sort new drug repositioning candidates for t-all identified via human/murine gene signature comparison
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680901/
https://www.ncbi.nlm.nih.gov/pubmed/33240808
http://dx.doi.org/10.3389/fonc.2020.557643
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