Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.
Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.
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DOI：
10.1158/0008-5472.can-09-3783
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发表时间：
2010-01-15
期刊：
影响因子：
11.2
通讯作者：
Verstovsek S
中科院分区：
文献类型：
--
作者：
Abdel-Wahab O;Manshouri T;Patel J;Harris K;Yao J;Hedvat C;Heguy A;Bueso-Ramos C;Kantarjian H;Levine RL;Verstovsek S
导致骨髓增殖性肿瘤（MPN）转化为急性髓系白血病（AML）的基因事件尚未明确。我们通过对63例继发于先前存在的MPN的AML（sAML）患者进行突变分析，研究了JAK2、TET2、ASXL1和IDH1突变在MPN白血病转化中的作用。我们在sAML中发现了频繁的TET2（26.3%）、ASXL1（19.3%）、IDH1（9.5%）和JAK2（36.8%）突变；观察到了这些基因所有可能的突变组合。对14例有MPN和sAML配对样本的患者进行分析表明，TET2突变在白血病转化时经常出现（6/14 = 43%）。相比之下，ASXL1突变几乎总是在个体患者的MPN和AML克隆中都能检测到。还观察到一个病例，在患者获得JAK2突变或出现MPN的临床证据之前就发现了TET2和ASXL1突变。我们得出结论，TET2、ASXL1和IDH1突变在源自先前存在的MPN的sAML中很常见。尽管TET2/ASXL1突变可能先于MPN克隆获得JAK2突变，但在白血病转化时通常会获得TET2突变，而不是ASXL1突变。这些数据表明，MPN和sAML中事件的突变顺序在不同患者中有所不同，并且TET2和ASXL1突变在MPN发病机制和白血病转化中具有不同的作用。存在没有先前存在的JAK2/TET2/ASXL1/IDH1突变的sAML，表明存在白血病转化所必需的其他突变。
The genetic events which contribute to transformation of myeloproliferative neoplasms (MPN) to acute myeloid leukemia (AML) are not well characterized. We investigated the role of JAK2, TET2, ASXL1, and IDH1 mutations in leukemic transformation of MPNs through mutational analysis of 63 patients with AML secondary to a preexisting MPN (sAML). We identified frequent TET2 (26.3%), ASXL1 (19.3%), IDH1 (9.5%), and JAK2 (36.8%) mutations in sAML; all possible mutational combinations of these genes were observed. Analysis of 14 patients for which paired samples from MPN and sAML were available demonstrated TET2 mutations were frequently acquired at leukemic transformation (6/14=43%). In contrast, ASXL1 mutations were almost always detected in both the MPN and AML clones from individual patients. A case was also observed where TET2 and ASXL1 mutations were found before the patient acquired a JAK2 mutation or developed clinical evidence of MPN. We conclude that mutations in TET2, ASXL1, and IDH1 are common in sAML derived from a pre-existing MPN. Although TET2/ASXL1 mutations may precede acquisition of JAK2 mutations by the MPN clone, mutations in TET2, but not ASXL1, are commonly acquired at the time of leukemic transformation. These data suggest the mutational order of events in MPN and sAML varies in different patients, and that TET2 and ASXL1 mutations have distinct roles in MPN pathogenesis and leukemic transformation. The presence of sAML with no pre-existing JAK2/TET2/ASXL1/IDH1 mutations indicates the existence of other mutations necessary for leukemic transformation.