Gene expression profiling of loss of TET2 and/or JAK2V617F mutant hematopoietic stem cells from mouse models of myeloproliferative neoplasms.
Gene expression profiling of loss of TET2 and/or JAK2V617F mutant hematopoietic stem cells from mouse models of myeloproliferative neoplasms.
复制标题
DOI：
10.1016/j.gdata.2015.04.002
复制
发表时间：
2015-06
期刊：
影响因子：
--
通讯作者：
Shimoda K
中科院分区：
文献类型：
--
作者：
Kameda T;Shide K;Yamaji T;Kamiunten A;Sekine M;Hidaka T;Kubuki Y;Sashida G;Aoyama K;Yoshimitsu M;Abe H;Miike T;Iwakiri H;Tahara Y;Yamamoto S;Hasuike S;Nagata K;Iwama A;Kitanaka A;Shimoda K
骨髓增生性肿瘤（MPN）的临床特征是分化的外周血细胞的慢性过度产生和恶性髓内/髓外造血的逐渐扩大。在超过90%的病例中，在MPN中JAK 2 MPL或CALR的突变是相互排斥的。它们中的突变导致JAK/STAT信号传导的异常激活和分化细胞的自主生长，因此它们被认为是“驱动”基因突变。除了上述驱动基因突变之外，在约5%-30%的病例中分别检测到表观遗传调节因子如TET 2、DNMT 3A、ASXL 1、EZH 2或IDH 1/2中的突变。TET 2、DNMT 3A、EZH 2或IDH 1/2中的突变通常赋予正常造血干细胞（HSC）增加的自我更新能力，但它们不会导致分化细胞的自主生长，并且仅表现出细微的临床表型[，5]。目前尚不清楚这些表观遗传调节因子中的突变如何影响具有驱动基因突变的异常HSC，它们如何影响疾病表型，或者单个驱动基因突变是否足以启动人类MPN。因此，我们专注于JAK 2 V617 F和TET 2的缺失-前者作为驱动基因突变的代表，后者作为表观遗传调节因子突变的代表-并通过功能分析和微阵列全基因组表达分析检查了单突变或双突变对HSC（谱系-Sca-1+c-Kit+细胞（LSK））的影响[9]。基因表达谱分析显示，与野生型LSK相比，HSC指纹基因[10]在TET 2敲低-LSK中统计学上同等富集，但在JAK 2 V617 F-LSK中负富集。在HSC指纹基因方面，双突变LSK与JAK 2 V617 F-LSK表现出相同的趋势，但两组之间单个基因的表达不同。在245个HSC指纹基因中，100个在双突变LSK中的表达高于JAK 2 V617 F-LSK。这些改变的基因表达可能部分解释了在功能分析中观察到的MPN的启动和进展机制[9]。在这里，我们描述了基因表达谱存放在基因表达综合（GEO）下的登录号GSE 62302，包括实验方法和质量控制分析。
Myeloproliferative neoplasms (MPNs) are clinically characterized by the chronic overproduction of differentiated peripheral blood cells and the gradual expansion of malignant intramedullary/extramedullary hematopoiesis. In MPNs mutations in JAK2 MPL or CALR are detected mutually exclusive in more than 90% of cases. Mutations in them lead to the abnormal activation of JAK/STAT signaling and the autonomous growth of differentiated cells therefore they are considered as “driver” gene mutations. In addition to the above driver gene mutations mutations in epigenetic regulators such as TET2 DNMT3A ASXL1 EZH2 or IDH1/2 are detected in about 5%–30% of cases respectively. Mutations in TET2 DNMT3A EZH2 or IDH1/2 commonly confer the increased self-renewal capacity on normal hematopoietic stem cells (HSCs) but they do not lead to the autonomous growth of differentiated cells and only exhibit subtle clinical phenotypes [,5]. It was unclear how mutations in such epigenetic regulators influenced abnormal HSCs with driver gene mutations how they influenced the disease phenotype or whether a single driver gene mutation was sufficient for the initiation of human MPNs. Therefore we focused on JAK2V617F and loss of TET2—the former as a representative of driver gene mutations and the latter as a representative of mutations in epigenetic regulators—and examined the influence of single or double mutations on HSCs (Lineage−Sca-1+c-Kit+ cells (LSKs)) by functional analyses and microarray whole-genome expression analyses [9]. Gene expression profiling showed that the HSC fingerprint genes [10] was statistically equally enriched in TET2-knockdown-LSKs but negatively enriched in JAK2V617F–LSKs compared to that in wild-type-LSKs. Double-mutant-LSKs showed the same tendency as JAK2V617F–LSKs in terms of their HSC fingerprint genes but the expression of individual genes differed between the two groups. Among 245 HSC fingerprint genes 100 were more highly expressed in double-mutant-LSKs than in JAK2V617F–LSKs. These altered gene expressions might partly explain the mechanisms of initiation and progression of MPNs which was observed in the functional analyses [9]. Here we describe gene expression profiles deposited at the Gene Expression Omnibus (GEO) under the accession number GSE62302 including experimental methods and quality control analyses.