Two Receptors, Two Isoforms, Two Cancers: Comprehensive Analysis of KIT and TrkA Expression in Neuroblastoma and Acute Myeloid Leukemia
Two Receptors, Two Isoforms, Two Cancers: Comprehensive Analysis of KIT and TrkA Expression in Neuroblastoma and Acute Myeloid Leukemia
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DOI：
10.3389/fonc.2019.01046
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发表时间：
2019-10-18
影响因子：
4.7
通讯作者：
Prassolov, Vladimir S.
中科院分区：
文献类型：
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作者：
Lebedev, Timofey D.;Vagapova, Elmira R.;Prassolov, Vladimir S.
儿童癌症代表了多种不同的肿瘤，尽管它们具有与成人癌症不同的独特特征。受体酪氨酸激酶 KIT 和 TrkA 分别在 AML 和 NB 中发挥作用，已得到充分表征。尽管在这两种肿瘤中都发现了这些受体的表达，但人们对于 NB 中的 KIT 和 AML 中的 TrkA 的功能知之甚少。通过将基因富集分析与多维尺度相结合，我们发现具有 t(8;21) 或 inv16 和高 KIT 表达水平的儿科 AML 从其他 AML 亚型中脱颖而出，因为它们仅与 KIT 过表达 NB 具有显着的转录组特征。我们发现 AML 细胞系主要表达另一种 TrkAIII 亚型，据报道该亚型具有致癌特征，而 NB 细胞系则主要表达 TrkAI-II 亚型。另一方面，与 AML 细胞相比，NB 细胞的 KIT 同工型比例异常。 SCF和NGF均对t(8;21) AML和NB细胞发挥针对多柔比星和阿糖胞苷的保护作用。我们确定了儿科 AML 和 NB 中独特和常见的几个基因集，并且这种表达与 KIT 或 TrkA 水平相关。 NMU、DUSP4、RET、SUSD5、NOS1 和 GABRA5 基因在 KIT 高表达的 NB 中差异表达，并且与 NB 的较差生存相关。我们鉴定出 HOXA10、BAG3 和 MARCKS 基因与 TrkA 表达相关，并且是 AML 预后不良的标记基因。我们还报告说，SLC18A2、PLXNC1 和 MRPL33 基因表达与 AML 和 NB 中的 TrkA 或 KIT 表达水平相关，这些基因对这两种癌症都具有预后价值。因此，我们提供了 TrkA 和 KIT 表达的全面表征以及这些基因在两个儿科肿瘤中的致癌特征。
Pediatric cancers represent a wide variety of different tumors, though they have unique features that distinguish them from adult cancers. Receptor tyrosine kinases KIT and TrkA functions in AML and NB, respectively, are well-characterized. Though expression of these receptors is found in both tumors, little is known about KIT function in NB and TrkA in AML. By combining gene enrichment analysis with multidimensional scaling we showed that pediatric AMLs with t(8;21) or inv16 and high KIT expression levels stand out from other AML subtypes as they share prominent transcriptomic features exclusively with KIT-overexpressing NBs. We showed that AML cell lines had a predominant expression of an alternative TrkAIII isoform, which reportedly has oncogenic features, while NB cell lines had dominating TrkAI-II isoforms. NB cells, on the other hand, had an abnormal ratio of KIT isoforms as opposed to AML cells. Both SCF and NGF exerted protective action against doxorubicin and cytarabine for t(8;21) AML and NB cells. We identified several gene sets both unique and common for pediatric AML and NB, and this expression is associated with KIT or TrkA levels. NMU, DUSP4, RET, SUSD5, NOS1, and GABRA5 genes are differentially expressed in NBs with high KIT expression and are associated with poor survival in NB. We identified HOXA10, BAG3, and MARCKS genes that are connected with TrkA expression and are marker genes of poor outcome in AML. We also report that SLC18A2, PLXNC1, and MRPL33 gene expression is associated with TrkA or KIT expression levels in both AML and NB, and these genes have a prognostic value for both cancers. Thus, we have provided a comprehensive characterization of TrkA and KIT expression along with the oncogenic signatures of these genes across two pediatric tumors.