Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms
Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms
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DOI：
10.1182/blood-2009-07-235119
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发表时间：
2010-04-08
期刊：
影响因子：
20.3
通讯作者：
Koeffler, H. Phillip
中科院分区：
文献类型：
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作者：
Thoennissen, Nils H.;Krug, Utz O.;Koeffler, H. Phillip
费城染色体阴性骨髓增生性肿瘤（MPN）包括真性红细胞增多症、原发性血小板增多症和原发性骨髓纤维化，表现出转化为白血病（MPN-母细胞期）的固有趋势，据推测这伴随着额外的基因组病变的获得。因此，我们通过高分辨率单核苷酸多态性（SNP）阵列检测了88例MPN患者和71例MPN急变期患者的染色体异常，并将这些发现与其临床参数相关联。在白血病转化后的MPN中发现了频繁的基因组改变，与慢性期样品相比，每个样品的基因组改变高达3倍（P <0.001）。我们确定了参与疾病进展的常见改变区域，不仅包括已确定的靶点（ETV 6，TP 53和RUNX 1），还包括7 q，16 q，19 p和21 q上的新候选基因。此外，8号三体或8 q24扩增（MYC）几乎只在JAK 2 V617 F（-）的MPN原始期病例中检测到。值得注意的是，包括纯合子JAK 2 V617 F在内的7 q或9 p上的拷贝数中性杂合性丢失（CNN-LOH）与白血病转化后生存率降低相关（分别为P = .01和P = .016）。我们的高密度SNP阵列分析MPN基因组在慢性与白血病阶段相比，确定了新的靶基因，并提供了预后的见解与白血病的演变。（血。2010; 115（14）：2882-2890）
Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and primary myelofibrosis show an inherent tendency for transformation into leukemia (MPN-blast phase), which is hypothesized to be accompanied by acquisition of additional genomic lesions. We, therefore, examined chromosomal abnormalities by high-resolution single nucleotide polymorphism (SNP) array in 88 MPN patients, as well as 71 cases with MPN-blast phase, and correlated these findings with their clinical parameters. Frequent genomic alterations were found in MPN after leukemic transformation with up to 3-fold more genomic changes per sample compared with samples in chronic phase (P < .001). We identified commonly altered regions involved in disease progression including not only established targets (ETV6, TP53, and RUNX1) but also new candidate genes on 7q, 16q, 19p, and 21q. Moreover, trisomy 8 or amplification of 8q24 (MYC) was almost exclusively detected in JAK2V617F(-) cases with MPN-blast phase. Remarkably, copy number-neutral loss of heterozygosity (CNN-LOH) on either 7q or 9p including homozygous JAK2V617F was related to decreased survival after leukemic transformation (P = .01 and P = .016, respectively). Our high-density SNP-array analysis of MPN genomes in the chronic compared with leukemic stage identified novel target genes and provided prognostic insights associated with the evolution to leukemia. (Blood. 2010; 115(14): 2882-2890)