文章：

分析基因组畸变和基因表达谱识别骨髓增殖性肿瘤的新病变和途径

Analysis of genomic aberrations and gene expression profiling identifies novel lesions and pathways in myeloproliferative neoplasms

原文发布日期：2011-11-11

DOI: 10.1038/bcj.2011.39

类型: Original Article

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英文摘要：

Polycythemia vera (PV), essential thrombocythemia and primary myelofibrosis, are myeloproliferative neoplasms (MPNs) with distinct clinical features and are associated with the JAK2V617F mutation. To identify genomic anomalies involved in the pathogenesis of these disorders, we profiled 87 MPN patients using Affymetrix 250K single-nucleotide polymorphism (SNP) arrays. Aberrations affecting chr9 were the most frequently observed and included 9pLOH (n=16), trisomy 9 (n=6) and amplifications of 9p13.3–23.3 (n=1), 9q33.1–34.13 (n=1) and 9q34.13 (n=6). Patients with trisomy 9 were associated with elevated JAK2V617F mutant allele burden, suggesting that gain of chr9 represents an alternative mechanism for increasing JAK2V617F dosage. Gene expression profiling of patients with and without chr9 abnormalities (+9, 9pLOH), identified genes potentially involved in disease pathogenesis including JAK2, STAT5B and MAPK14. We also observed recurrent gains of 1p36.31–36.33 (n=6), 17q21.2–q21.31 (n=5) and 17q25.1–25.3 (n=5) and deletions affecting 18p11.31–11.32 (n=8). Combined SNP and gene expression analysis identified aberrations affecting components of a non-canonical PRC2 complex (EZH1, SUZ12 and JARID2) and genes comprising a ‘HSC signature’ (MLLT3, SMARCA2 and PBX1). We show that NFIB, which is amplified in 7/87 MPN patients and upregulated in PV CD34+ cells, protects cells from apoptosis induced by cytokine withdrawal.

摘要翻译： 

真性红细胞增多症、原发性血小板增多症及原发性骨髓纤维化均属具有独特临床特征的JAK2V617F突变相关骨髓增殖性肿瘤。为探究这些疾病的致病基因组异常，我们采用Affymetrix 250K单核苷酸多态性芯片对87例MPN患者进行分析。9号染色体异常最为常见，包括9p杂合性缺失（16例）、9号染色体三体（6例）及9p13.3–23.3区（1例）、9q33.1–34.13区（1例）和9q34.13区（6例）扩增。9号染色体三体患者伴随JAK2V617F突变等位基因负荷升高，提示染色体9增益是增加JAK2V617F剂量的替代机制。通过对比有无9号染色体异常（+9、9pLOH）患者的基因表达谱，我们发现JAK2、STAT5B和MAPK14等基因可能参与疾病发生。同时观察到1p36.31–36.33区（6例）、17q21.2–q21.31区（5例）和17q25.1–25.3区（5例）的反复增益及18p11.31–11.32区缺失（8例）。联合SNP与基因表达分析发现影响非经典PRC2复合体（EZH1、SUZ12和JARID2）的异常，以及构成“造血干细胞特征基因”（MLLT3、SMARCA2和PBX1）的异常。研究显示在7/87例MPN患者中扩增并于真红CD34+细胞中上调的NFIB基因，能保护细胞免于细胞因子剥夺诱导的凋亡。

原文链接：

Analysis of genomic aberrations and gene expression profiling identifies novel lesions and pathways in myeloproliferative neoplasms