What is the role of JAK2(V617F) mutation in leukemic transformation of myeloproliferative neoplasms?
What is the role of JAK2(V617F) mutation in leukemic transformation of myeloproliferative neoplasms?
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DOI：
10.1532/lh96.10018
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发表时间：
2011-03-01
期刊：
影响因子：
--
通讯作者：
de Sousa, Aida Botelho
中科院分区：
文献类型：
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作者：
Lopes da Silva, Rodrigo;Ribeiro, Patricia;de Sousa, Aida Botelho
背景和目的：Janus 激酶 2 V617F (JAK2(V617F)) 突变在各种 BCR-ABL1 阴性骨髓增生性肿瘤 (MPN) 发病机制中的作用仍不清楚。它在白血病转化中的意义是一个更具争议性的问题。本研究的目的是评估我机构发生急变危象的罕见病例的 JAK2(V617F) 突变状态以及强化治疗后的反应。 材料和方法：1999 年至 2009 年间，我中心 778 例诊断为 BCR-ABL1 阴性 MPN 的患者（真性红细胞增多症 395 例，原发性血小板增多症 329 例，原发性血小板增多症 45 例）。骨髓纤维化病例，以及 9 例无法以其他方式分类的 MPN 病例）。这些患者中，7 人发生了白血病转化。采用扩增阻滞突变系统对JAK2(V617F)突变进行基因分型。结果：7例患者中有6例在疾病慢性期进行了JAK2(V617F)检测，其中3例患者JAK2(V617F)呈阳性。这些患者（2 名患有真性红细胞增多症和 1 名患有原发性血小板增多症）在急变期甚至其中一名患者经过强化治疗后也携带杂合状态的 JAK2（V617F）。其他进化为急变危机的病例在转化前后均未携带JAK2(V617F)突变。尽管进行了常规或支持治疗，所有 7 名患者均死亡。结论：MPN 转化为急性白血病本身是一种非常罕见的现象，急变期后 JAK2（V617F）突变的持续存在也是如此。在我们的系列中，所有 JAK2(V617F) 阳性患者在白血病转化后仍保持该突变阳性，尽管处于杂合状态，这表明 JAK2(V617F) 对于这些病例中的转化并不是必需的。所有 JAK2(V617F) 阴性病例在急变后仍呈阴性这一事实强化了其他分子事件可能在 MPN 克隆异质性中发挥作用的理论。由于继发于 MPN 的急性髓系白血病预后不佳，患者应被纳入新型 JAK2 抑制剂的临床试验中。
BACKGROUND AND OBJECTIVES: The role of the Janus kinase 2 V617F (JAK2(V617F)) mutation in the pathogenesis of the various BCR-ABL1-negative myeloproliferative neoplasms (MPNs) remains unclear. Its significance in leukemic transformation is a matter of even greater controversy. The aim of this study was to evaluate both the JAK2(V617F) mutational status of the rare cases in which blast crisis occurred in our institution and the response after intensive treatment.MATERIALS AND METHODS: Between 1999 and 2009, 778 patients received diagnoses of BCR-ABL1-negative MPNs in our center (395 polycythemia vera, 329 essential thrombocythemia, and 45 primary myelofibrosis cases, as well as 9 MPN cases not otherwise classifiable). Of these patients, 7 developed leukemic transformation. The genotyping of the JAK2(V617F) mutation was performed by the amplification-refractory mutation system.RESULTS: Six of the 7 patients were tested for JAK2(V617F) in the chronic phase of their disease, and 3 of these patients were positive for JAK2(V617F). These patients, 2 with polycythemia vera and 1 with essential thrombocythemia, also harbored JAK2(V617F) in the heterozygous state during blast crisis and even after intensive treatment in one of these patients. The other cases that evolved to blast crisis did not harbor the JAK2(V617F) mutation before and after transformation. All 7 patients died despite conventional or supportive treatment.CONCLUSIONS: The transformation of MPNs into acute leukemia is by itself a very rare phenomenon, and so is the persistence of the JAK2(V617F) mutation after blast crisis. In our series, all JAK2(V617F)-positive patients remained positive for this mutation after leukemic transformation, although in the heterozygous state, suggesting that JAK2(V617F) is not essential for transformation in these cases. The fact that all JAK2(V617F)-negative cases remained negative after blast crisis reinforces the theory that other molecular event(s) may play a role in the clonal heterogeneity of MPNs. Owing to the poor outcome of acute myeloid leukemia secondary to MPN, patients should be included in clinical trials of the novel JAK2 inhibitors.