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: 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.
Highlights
Treatments for acute lymphoblastic leukemia (ALL) are improving as the overall survival rate at five years from diagnosis raised from 12% in 1960 to 65% in 2014 and around 80% nowadays [1]
We confronted transcriptomic data obtained from human T-cell Acute Lymphoblastic Leukemia (T-ALL) gene signatures present in public datasets to the one we established from a tPTEN-/- T-ALL mouse model, to highlight the gene dysregulations that could be shared between the two models
Using data from tPTEN-/- cells could be a bias as PTEN mutations are observed in only 15%– 20% of the cases, it has to be kept in mind that the PI3K/Akt/mTOR pathway negatively controlled by PTEN is abnormally active in almost 90% of T-ALL cases
Summary
Treatments for acute lymphoblastic leukemia (ALL) are improving as the overall survival rate at five years from diagnosis raised from 12% in 1960 to 65% in 2014 and around 80% nowadays [1]. 70% of T-ALL have lost the P16/ INK4A, P19/ARF tumor suppressors leading to unrestrained stimulation of cyclin-CDK complexes and cell cycle progression on one arm and inactivation of the p53 tumor suppressor response on the other. These dysregulated events are being investigated as targets of future treatments [5, 13]. Ex vivo drug profiling to evaluate the chemosensitivity of relapse samples could be another powerful approach to propose new therapeutic options for some TALL subgroups or individual patients [14]
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