Effect of mutation order on myeloproliferative neoplasms.
Effect of mutation order on myeloproliferative neoplasms.
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DOI：
10.1056/nejmoa1412098
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发表时间：
2015-02-12
期刊：
影响因子：
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通讯作者：
Green AR
中科院分区：
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作者：
Ortmann CA;Kent DG;Nangalia J;Silber Y;Wedge DC;Grinfeld J;Baxter EJ;Massie CE;Papaemmanuil E;Menon S;Godfrey AL;Dimitropoulou D;Guglielmelli P;Bellosillo B;Besses C;Döhner K;Harrison CN;Vassiliou GS;Vannucchi A;Campbell PJ;Green AR
癌症是体细胞突变积累的结果，它们的特性被认为反映了这些突变的总和。然而，人们对获得突变的顺序的影响知之甚少。我们通过对造血集落进行基因分型或通过下一代测序的方法来确定骨髓增殖性肿瘤患者的突变顺序。分离干细胞和祖细胞，研究突变顺序对成熟和未成熟造血细胞的影响。患者出现骨髓增殖性肿瘤的年龄、JAK2 V617F纯合子的获得以及未成熟祖细胞的平衡都受到突变顺序的影响。与首先获得TET2突变的患者(以下称为“TET2-First患者”)相比，首先获得Janus Kinase 2(JAK2)突变的患者(“JAK2-First患者”)出现真性红细胞增多症的可能性比出现特发性血小板增多症的可能性更大，血栓形成的风险增加，JAK2突变的祖细胞体外对Ruxolitinib的敏感性增加。突变顺序影响对JAK2 V617F的增殖反应以及双突变造血细胞和祖细胞产生集落形成细胞的能力。此外，在TET2-First患者中，TET2单突变细胞占主导地位，而在JAK2-First患者中，则由JAK2-TET2双突变细胞主导。TET2的先前突变以细胞固有的方式改变了JAK2V617F的转录结果，并阻止JAK2V617F上调与增殖相关的基因。获得JAK2和TET2突变的顺序影响骨髓增殖性肿瘤患者的临床特征、靶向治疗的反应、干细胞和祖细胞的生物学以及克隆进化。(由白血病和淋巴瘤研究和其他机构资助。)
Cancers result from the accumulation of somatic mutations, and their properties are thought to reflect the sum of these mutations. However, little is known about the effect of the order in which mutations are acquired. We determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 mutation was acquired first (hereafter referred to as “TET2-first patients”), patients in whom the Janus kinase 2 (JAK2) mutation was acquired first (“JAK2-first patients”) had a greater likelihood of presenting with polycythemia vera than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2–TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from up-regulating genes associated with proliferation. The order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. (Funded by Leukemia and Lymphoma Research and others.)