Votavova Hana, Urbanova Zuzana, Kundrat David, Dostalova Merkerova Michaela, Vostry Martin, Hruba Monika, Cermak Jaroslav, Belickova Monika
Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague, Czech Republic.
First Faculty of Medicine, Charles University, Katerinská 32, 121 08 Prague, Czech Republic.
Pharmaceuticals (Basel). 2021 Jan 7;14(1):41. doi: 10.3390/ph14010041.
Deferasirox (DFX) is an oral iron chelator used to reduce iron overload (IO) caused by frequent blood cell transfusions in anemic myelodysplastic syndrome (MDS) patients. To study the molecular mechanisms by which DFX improves outcome in MDS, we analyzed the global gene expression in untreated MDS patients and those who were given DFX treatment. The gene expression profiles of bone marrow CD34 cells were assessed by whole-genome microarrays. Initially, differentially expressed genes (DEGs) were determined between patients with normal ferritin levels and those with IO to address the effect of excessive iron on cellular pathways. These DEGs were annotated to Gene Ontology terms associated with cell cycle, apoptosis, adaptive immune response and protein folding and were enriched in cancer-related pathways. The deregulation of multiple cancer pathways in iron-overloaded patients suggests that IO is a cofactor favoring the progression of MDS. The DEGs between patients with IO and those treated with DFX were involved predominantly in biological processes related to the immune response and inflammation. These data indicate DFX modulates the immune response mainly via neutrophil-related genes. Suppression of negative regulators of blood cell differentiation essential for cell maturation and upregulation of heme metabolism observed in DFX-treated patients may contribute to the hematopoietic improvement.
地拉罗司（DFX）是一种口服铁螯合剂，用于降低贫血性骨髓增生异常综合征（MDS）患者因频繁输血导致的铁过载（IO）。为了研究DFX改善MDS患者预后的分子机制，我们分析了未经治疗的MDS患者和接受DFX治疗患者的全基因组表达情况。通过全基因组微阵列评估骨髓CD34细胞的基因表达谱。最初，在铁蛋白水平正常的患者和有铁过载的患者之间确定差异表达基因（DEG），以研究过量铁对细胞通路的影响。这些DEG被注释到与细胞周期、凋亡、适应性免疫反应和蛋白质折叠相关的基因本体论术语，并在癌症相关通路中富集。铁过载患者中多种癌症通路的失调表明，铁过载是促进MDS进展的一个辅助因素。有铁过载的患者与接受DFX治疗的患者之间的DEG主要参与与免疫反应和炎症相关的生物学过程。这些数据表明，DFX主要通过与中性粒细胞相关的基因调节免疫反应。在接受DFX治疗的患者中观察到，对细胞成熟至关重要的血细胞分化负调节因子受到抑制，血红素代谢上调，这可能有助于造血功能的改善。
