Mutation in TET2 in Myeloid Cancers
Mutation in TET2 in Myeloid Cancers
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DOI：
10.1056/nejmoa0810069
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发表时间：
2009-05-28
影响因子：
158.5
通讯作者：
Bernard, Olivier A.
中科院分区：
文献类型：
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作者：
Delhommeau, Francois;Dupont, Sabrina;Bernard, Olivier A.
背景骨髓增生异常综合征和骨髓增生性疾病与髓系细胞的分泌失调有关。我们通过分子、细胞遗传学、比较基因组杂交和单核苷酸多态性分析相结合的方法，确定了骨髓增生异常综合征、骨髓增殖性疾病和急性髓系白血病(AML)患者常见的候选抑癌基因。对320例患者进行了该基因TET2的编码序列测定。我们通过体外克隆分析和将人类肿瘤细胞移植到小鼠体内，分析了TET2基因缺失或突变的后果。结果我们最初在3例骨髓增生异常综合征患者、3例骨髓增生性疾病患者、2例原发AML患者和1例继发性AML患者中发现了TET2基因缺失或突变。我们选择了6名骨髓增生异常综合征或AML患者，因为他们携带了染色体4q24上的获得性重排；我们选择了5名骨髓增殖性疾病患者，因为他们在造血祖细胞中携带了一个显性克隆，该克隆对Janus kinase2(JAK2)基因中的V617F突变阳性。81例骨髓增生异常综合征患者中15例(19%)、198例骨髓增生性疾病患者中24例(12%)(伴有或不伴有JAK2 V617F突变)、21例继发性AML患者中5例(24%)、9例慢性单核细胞白血病患者中2例(22%)出现TET2缺陷。在我们分析的5例骨髓增生性疾病患者中，造血干细胞中存在TET2缺陷，并且先于JAK2 V617F突变。结论约15%的各种髓系肿瘤患者存在TET2体细胞突变。
BACKGROUNDThe myelodysplastic syndromes and myeloproliferative disorders are associated with deregulated production of myeloid cells. The mechanisms underlying these disorders are not well defined.METHODSWe conducted a combination of molecular, cytogenetic, comparative-genomic-hybridization, and single-nucleotide-polymorphism analyses to identify a candidate tumor-suppressor gene common to patients with myelodysplastic syndromes, myeloproliferative disorders, and acute myeloid leukemia (AML). The coding sequence of this gene, TET2, was determined in 320 patients. We analyzed the consequences of deletions or mutations in TET2 with the use of in vitro clonal assays and transplantation of human tumor cells into mice.RESULTSWe initially identified deletions or mutations in TET2 in three patients with myelodysplastic syndromes, in three of five patients with myeloproliferative disorders, in two patients with primary AML, and in one patient with secondary AML. We selected the six patients with myelodysplastic syndromes or AML because they carried acquired rearrangements on chromosome 4q24; we selected the five patients with myeloproliferative disorders because they carried a dominant clone in hematopoietic progenitor cells that was positive for the V617F mutation in the Janus kinase 2 (JAK2) gene. TET2 defects were observed in 15 of 81 patients with myelodysplastic syndromes (19%), in 24 of 198 patients with myeloproliferative disorders (12%) (with or without the JAK2 V617F mutation), in 5 of 21 patients with secondary AML (24%), and in 2 of 9 patients with chronic myelomonocytic leukemia (22%). TET2 defects were present in hematopoietic stem cells and preceded the JAK2 V617F mutation in the five samples from patients with myeloproliferative disorders that we analyzed.CONCLUSIONSSomatic mutations in TET2 occur in about 15% of patients with various myeloid cancers.