Dataset Information

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

ABSTRACT: 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: ?-estradiol (?-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.

SUBMITTER: Bonnet R

PROVIDER: S-EPMC7680901 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Bonnet Raphaël R Nebout Marielle M Brousse Carine C Reinier Frédéric F Imbert Véronique V Rohrlich Pierre Simon PS Peyron Jean-François JF

Frontiers in oncology 20201109

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 ...[more]

PMID: 33240808

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Dataset Information

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

Publications

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

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