T-cell Acute Lymphoblastic Leukemia Cells Display Activation of Different Survival Pathways
T-cell Acute Lymphoblastic Leukemia Cells Display Activation of Different Survival Pathways
复制标题
T 细胞急性淋巴细胞白血病细胞表现出不同生存途径的激活
作者：
Sausan A. Moharram;K. Shah;Julhash U. Kazi
T细胞急性淋巴细胞白血病（T-ALL）是一种影响T淋巴细胞的血液疾病。尽管T-ALL治疗取得了显著的改善，但仍有一半的成人T-ALL患者经历治疗失败。为了开发靶向治疗，我们需要更好地了解T-ALL的发病机制。在这项研究中，我们使用了患者来源的细胞系显示耐糖皮质激素。我们观察到不同的细胞系依赖于不同的生存信号通路。AKT、p38、S6 K或ERK信号传导的异常激活在所研究的所有细胞系中未发现相同程度。为了了解T-ALL细胞的分子差异，我们比较了基因表达和体细胞突变。基因集富集分析显示mTORC 1、MAPK或TGF-β信号通路的富集。在研究的所有细胞系中鉴定了TP 53和FBXW 7基因的功能丧失突变。因此，我们认为来自不同患者的T-ALL细胞对不同的突变上瘾，从而对不同的信号通路上瘾。因此，了解每个个体患者的分子途径富集将为我们提供更精确和具体的治疗计划。
T-cell acute lymphoblastic leukemia (T-ALL) is a disease of the blood affecting T-lymphocytes. Although notable improvements have been achieved in T-ALL treatment, half of the adult T-ALL patients still experience treatment failure. In order to develop a targeted therapy, we need a better understanding of T-ALL pathogenesis. In this study, we used patient-derived cell lines which display resistance to glucocorticoids. We observed that different cell lines are dependent on different survival signaling pathways. Aberrant activation of AKT, p38, S6K or ERK signaling was not found to the same degree in all cell lines studied. To understand the molecular differences in T-ALL cells, we compared gene expression and somatic mutations. Gene set enrichment analysis showed enrichment of the mTORC1, MAPK or TGF-beta signaling pathways. Loss-of-function mutations in the TP53 and FBXW7 genes were identified in all cell lines investigated. Thus, we suggest that T-ALL cells from different patients are addicted to different mutations and thereby to different signaling pathways. Therefore, understanding the enrichment of molecular pathways for each individual patient will provide us with a more precise and specific treatment plan.