Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome.
Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome.
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DOI：
10.1182/blood-2011-11-390252
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发表时间：
2012-05
期刊：
影响因子：
20.3
通讯作者：
Sujiang Zhang;R. Rampal;T. Manshouri;Jay P. Patel;Nana Mensah;Andrew Kayserian;Todd Hricik;A. Heguy;C. Hedvat;M. Gönen;H. Kantarjian;R. Levine;O. Abdel-Wahab;S. Verstovsek
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文献类型：
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作者：
Sujiang Zhang;R. Rampal;T. Manshouri;Jay P. Patel;Nana Mensah;Andrew Kayserian;Todd Hricik;A. Heguy;C. Hedvat;M. Gönen;H. Kantarjian;R. Levine;O. Abdel-Wahab;S. Verstovsek
骨髓增生性肿瘤(MPN)的白血病转化(LT)与预后不良和治疗抵抗有关。尽管之前的候选遗传学研究已经证实了MPN患者发生急性白血病的突变，但接受LT的MPN患者的基因异常补充尚不清楚，也没有证据表明特定的分子异常在这种情况下具有临床意义。我们对53例MPN术后LT患者的22个基因进行了高通量重测序，以表征该实体中已知的髓系突变的频率。除了MPN后LT中常见的JAK2和TET2突变外，我们还在MPN转化的急性髓系白血病(AML)中发现了富含丝氨酸/精氨酸的剪接因子2(SRSF2)基因的反复突变(18.9%)。与骨髓发育不良(4.8%)和初治AML(5.6%)后相比，起源于MPN的AML中SRSF2突变更常见(P=0.05)。重要的是，在单变量(P=0.03；HR，2.77；95%CI，1.10-7.00)和多因素分析(P<；0.05；HR，2.11；95%CI，1.01-4.42)中，SRSF2突变与接受LT的MPN患者的总生存率恶化有关。这些数据表明，SRSF2突变参与了LT的发病机制，并可能指导接受LT的MPN患者的新治疗方法。
Leukemic transformation (LT) of myeloproliferative neoplasms (MPNs) is associated with a poor prognosis and resistance to therapy. Although previous candidate genetic studies have identified mutations in MPN patients who develop acute leukemia, the complement of genetic abnormalities in MPN patients who undergo LT is not known nor have specific molecular abnormalities been shown to have clinical relevance in this setting. We performed high-throughput resequencing of 22 genes in 53 patients with LT after MPN to characterize the frequency of known myeloid mutations in this entity. In addition to JAK2 and TET2 mutations, which occur commonly in LT after MPN, we identified recurrent mutations in the serine/arginine-rich splicing factor 2 (SRSF2) gene (18.9%) in acute myeloid leukemia (AML) transformed from MPNs. SRSF2 mutations are more common in AML derived from MPNs compared with LT after myelodysplasia (4.8%) or de novo AML (5.6%), respectively (P=.05). Importantly, SRSF2 mutations are associated with worsened overall survival in MPN patients who undergo LT in univariate (P=.03; HR, 2.77; 95% CI, 1.10-7.00) and multivariate analysis (P<.05; HR, 2.11; 95% CI, 1.01-4.42). These data suggest that SRSF2 mutations contribute to the pathogenesis of LT and may guide novel therapeutic approaches for MPN patients who undergo LT.