Bonnet Raphaël, Nebout Marielle, Brousse Carine, Reinier Frédéric, Imbert Véronique, Rohrlich Pierre Simon, Peyron Jean-François
Université Côte d'Azur, INSERM, C3M, Nice, France.
Pediatric Hematology-Oncology, CHU de Nice, Nice, France.
Front Oncol. 2020 Nov 9;10:557643. doi: 10.3389/fonc.2020.557643. eCollection 2020.
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 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 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.
T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性白血病亚型，在过去几十年中，其治疗效率取得了重要进展，如今治愈率达到了75%-80%。然而，由于复发与非常糟糕的预后相关，因此必须寻找新的靶点和活性分子用于创新治疗策略。我们设计了一个实验工作流程，通过将人类T-ALL病例的基因表达谱（GEP）与小鼠T-ALL代表性模型的GEP进行对比，以突出与白血病发生相关的保守核心通路，该小鼠模型是通过在T细胞前体中条件性缺失肿瘤抑制基因（tPTEN-/-）产生的。我们鉴定出844个差异表达基因，即人类T-ALL和小鼠特征之间保守的共同GEP（cGEP），与正常T细胞相比，它们也有类似的差异表达。使用生物信息学工具，我们在cGEP中突出显示了E2F、MYC和mTORC1的上调。接下来，使用连通性图谱（CMAP）以及我们开发的CMAP数据可视化程序CMAPViz，我们选择了三种FDA批准的生物活性分子候选物：α-雌二醇（α-E）、去甲二氢愈创木酸（NDGA）和马来酸氯丙嗪（PCZ）。在生物学水平上，我们表明这三种药物在一组T-ALL细胞系中引发了凋亡性细胞死亡，激活了DNA损伤反应，并干扰了组成性mTORC1激活和c-MYC表达。该分析表明，研究保守的白血病发生途径可能是揭示药理学干预新途径的一种策略。
