Mesh ： 1-Methyl-3-isobutylxanthine / pharmacology Animals Antineoplastic Combined Chemotherapy Protocols / therapeutic use Cell Line, Tumor Child Chromogranins / antagonists & inhibitors Colforsin / pharmacology Cyclic AMP / pharmacology physiology Dexamethasone / administration & dosage pharmacology Dinoprostone / administration & dosage antagonists & inhibitors pharmacology physiology Drug Resistance, Neoplasm / genetics physiology Female GTP-Binding Protein alpha Subunits, Gs / antagonists & inhibitors deficiency Gene Expression Regulation, Leukemic / drug effects Humans Male Mice Models, Animal Molecular Targeted Therapy Neoplasm Proteins / biosynthesis genetics Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy metabolism pathology RNA Interference RNA, Small Interfering / genetics pharmacology Radiation Chimera Receptors, Glucocorticoid / biosynthesis genetics physiology Receptors, Prostaglandin E, EP4 Subtype / biosynthesis genetics Second Messenger Systems / drug effects Xenograft Model Antitumor Assays

来  源：   DOI：10.1182/blood.2020005712   PDF(Sci-hub)   PDF(Pubmed)

Abstract：
Glucocorticoid (GC) resistance remains a clinical challenge in pediatric acute lymphoblastic leukemia where response to GC is a reliable prognostic indicator. To identify GC resistance pathways, we conducted a genome-wide, survival-based, short hairpin RNA screen in murine T-cell acute lymphoblastic leukemia (T-ALL) cells. Genes identified in the screen interfere with cyclic adenosine monophosphate (cAMP) signaling and are underexpressed in GC-resistant or relapsed ALL patients. Silencing of the cAMP-activating Gnas gene interfered with GC-induced gene expression, resulting in dexamethasone resistance in vitro and in vivo. We demonstrate that cAMP signaling synergizes with dexamethasone to enhance cell death in GC-resistant human T-ALL cells. We find the E prostanoid receptor 4 expressed in T-ALL samples and demonstrate that prostaglandin E2 (PGE2) increases intracellular cAMP, potentiates GC-induced gene expression, and sensitizes human T-ALL samples to dexamethasone in vitro and in vivo. These findings identify PGE2 as a target for GC resensitization in relapsed pediatric T-ALL.
摘要：
糖皮质激素（GC）耐药性仍然是小儿急性淋巴细胞白血病的临床挑战，其中对GC的反应是可靠的预后指标。为了确定GC抗性途径，我们进行了全基因组，以生存为基础，短发夹RNA筛选小鼠T细胞急性淋巴细胞白血病（T-ALL）细胞。筛选中鉴定的基因干扰环磷酸腺苷（cAMP）信号，并在GC抗性或复发性ALL患者中表达不足。cAMP激活Gnas基因的沉默干扰了GC诱导的基因表达，在体外和体内产生地塞米松抗性。我们证明了cAMP信号与地塞米松协同增强GC抗性人T-ALL细胞的细胞死亡。我们发现在T-ALL样品中表达的E类前列腺素受体4，并证明前列腺素E2（PGE2）增加细胞内cAMP，增强GC诱导的基因表达，并在体外和体内对人T-ALL样品对地塞米松敏感。这些发现将PGE2确定为复发性小儿T-ALL中GC再敏化的靶标。
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