Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis
Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis
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DOI：
10.1182/blood-2014-02-554634
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发表时间：
2014-05-29
期刊：
影响因子：
20.3
通讯作者：
Levine, Ross L.
中科院分区：
文献类型：
--
作者：
Rampal, Raajit;Al-Shahrour, Fatima;Levine, Ross L.
基因组研究已经在大多数骨髓增生性肿瘤（MPN）患者中发现了体细胞改变，包括大多数MPN患者中的JAK 2突变和JAK 2阴性MPN患者中的CALR突变。然而，JAK-STAT通路激活在不同的MPN中的作用，以及在没有JAK 2突变的患者中的作用，尚未得到明确的描述。我们使用表达谱、单核苷酸多态性阵列和突变谱来研究一组特征明确的MPN患者。JAK 2 V617 F纯合突变的MPN患者的特征在于独特的转录谱。值得注意的是，无论临床表型或突变状态如何，在所有MPN患者中均观察到与激活的JAK 2信号一致的转录特征。此外，激活的JAK 2标签存在于具有体细胞CALR突变的患者中。相反，Wei鉴定了CALR突变的基因表达特征;该特征在JAK 2突变的MPN患者中显著富集，这与JAK 2和CALR突变的共同转化机制一致。我们还鉴定了MPN患者样本中TET 2突变的转录特征。我们的数据表明，MPN患者，无论诊断或JAK 2突变状态，其特征在于具有JAK-STAT靶基因上调的独特基因表达特征，证明了JAK-STAT途径在MPN发病机制中的核心重要性。
Genomic studies have identified somatic alterations in the majority of myeloproliferative neoplasms (MPN) patients, including JAK2 mutations in the majority of MPN patients and CALR mutations in JAK2-negative MPN patients. However, the role of JAK-STAT pathway activation in different MPNs, and in patients without JAK2 mutations, has not been definitively delineated. We used expression profiling, single nucleotide polymorphism arrays, and mutational profiling to investigate a well-characterized cohort of MPN patients. MPN patients with homozygous JAK2V617F mutations were characterized by a distinctive transcriptional profile. Notably, a transcriptional signature consistent with activated JAK2 signaling is seen in allMPN patients regardless of clinical phenotype ormutational status. In addition, the activated JAK2 signature was present in patients with somaticCALRmutations. Conversely, weidentified a gene expression signature ofCALRmutations; this signaturewas significantly enriched in JAK2-mutant MPN patients consistent with a shared mechanism of transformation by JAK2 and CALR mutations. We also identified a transcriptional signature of TET2 mutations in MPN patent samples. Our data indicate that MPN patients, regardless of diagnosis or JAK2 mutational status, are characterized by a distinct gene expression signature with upregulation of JAK-STAT target genes, demonstrating the central importance of the JAK-STAT pathway in MPN pathogenesis.