Mutation of JAK2 in the myeloproliferative disorders:: timing, clonality studies, cytogenetic associations, and role in leukemic transformation
Mutation of JAK2 in the myeloproliferative disorders:: timing, clonality studies, cytogenetic associations, and role in leukemic transformation
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DOI：
10.1182/blood-2005-12-013748
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发表时间：
2006-11-15
期刊：
影响因子：
20.3
通讯作者：
Green, Anthony R.
中科院分区：
文献类型：
--
作者：
Campbell, Peter J.;Baxter, E. Joanna;Green, Anthony R.
在骨髓增生性疾病患者中JAK 2获得性突变的鉴定提出了关于突变阳性和突变阴性亚型之间的关系，JAK 2突变的时间和疾病进展的分子机制的问题。在这里，我们证明V617 F（-）原发性血小板增多症患者通常不会进展为V617 F（+）。与不同的发病机制的概念相一致，我们发现，有和没有JAK 2突变的患者具有不同的细胞遗传学异常模式，几乎所有携带20 q缺失或9三体的患者都是V617 F（+）。我们还通过比较从X染色体失活模式（XCIP）估计的克隆来源的粒细胞的比例与V617 F（+）粒细胞的比例，研究了“前JAK 2”阶段的存在。我们的研究结果表明，粒细胞和T细胞之间固有的XCIP变异性产生了一个系统性的偏倚模式的结果，可能被误解为证据过量的克隆衍生的粒细胞，观察，限制了XCIP分析在这种情况下的效用。最后，我们研究了4例V617 F（+）骨髓增生性疾病患者，他们随后发展为急性髓性白血病。3例患者的白血病细胞为V617 F（-），表明这些患者的白血病发生在V617 F（-）细胞中。
The identification of an acquired mutation of JAK2 in patients with myeloproliferative disorders has raised questions about the relationship between mutation-positive and mutation-negative subtypes, timing of the JAK2 mutation, and molecular mechanisms of disease progression. Here we demonstrate that patients with V617F(-) essential thrombocythemia do not commonly progress to become V617F(+). Consistent with the concept of distinct pathogenetic mechanisms, we show that patients with and without the JAK2 mutation have different patterns of cytogenetic abnormality, with virtually all patients carrying the 20q deletion or trisomy 9 being V617F(+). We also investigated the existence of a "pre-JAK2" phase by comparing the proportion of clonally derived granulocytes, estimated from X-chromosome inactivation patterns (XCIPs), with the proportion of V617F(+) granulocytes. Our results demonstrate that inherent XCIP variability between granulocytes and T cells produces a systematically biased pattern of results that may be misinterpreted as evidence for an excess of clonally derived granulocytes, an observation that limits the utility of XCIP analysis in this context. Lastly, we studied 4 patients with V617F(+) myeloproliferative disorders who subsequently developed acute myeloid leukemia. In 3 patients the leukemic cells were V617F(-), suggesting that in these patients the leukemia arose in a V617F(-) cell.