Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation
Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation
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DOI：
10.1182/blood-2004-02-0754
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发表时间：
2004-09-01
期刊：
影响因子：
20.3
通讯作者：
Pedersen-Bjergaard, J
中科院分区：
文献类型：
--
作者：
Christiansen, DH;Andersen, MK;Pedersen-Bjergaard, J
AML1转录因子是正常造血所必需的，也是急性白血病几种染色体易位的靶标。新发骨髓发育不良(MDS)和急性髓系白血病(AML)，包括少数治疗相关疾病(t-MDS/t-AML)，最近零星发现获得性体细胞AML1突变。我们用直接测序法检测了140例t-MDS或t-AML患者的AML1突变。我们在22例患者中发现了9个错义突变、3个无义突变和10个移码突变，这些突变都是杂合子。13个突变位于N-末端Run同源结构域(RHD)，9个突变位于C-末端，包括反式激活结构域(TAD)。19名AML1突变患者以前接受过烷基化药物治疗，而2名患者仅接受过放射治疗。AML1突变与t-MDS(P=.003)、7q染色体缺失或丢失(P=.001)以及随后转化为显性t-AML(P=.0001)密切相关。与无义/移码突变患者相比，错义突变患者的生存期更短(P=0.03)。我们的结果提示，AML1突变和染色体7q上基因的缺失在白血病的发生中起协同作用，并易发生白血病转化。(C)2004年由美国人。
The AML1 transcription factor is essential for normal hematopoiesis and is the target of several chromosomal translocations in acute leukemia. Acquired somatic AML1 mutations were recently demonstrated sporadically in de novo myelodysplasia (MDS) and acute myeloid leukemia (AML) including a few cases of therapy-related disease (t-MDS/t-AML). We examined 140 patients with t-MDS or t-AML for AML1 mutations by direct sequencing. We identified 9 missense, 3 nonsense, and 10 frameshift mutations, all heterozygous, in 22 patients (15.7%). Thirteen mutations were located in the N-terminal Runt homology domain (RHD), whereas 9 mutations were located in the C-terminal region including the transactivation domain (TAD). Nineteen patients with AML1 mutations had previously received alkylating agents whereas 2 patients had received radiotherapy only. AML1 mutations were highly significantly associated with presentation of the disease as t-MDS (P = .003), with deletion or loss of chromosome arm 7q (P = .001) and with subsequent transformation to overt t-AML (P = .0001). Patients with missense mutations presented a shorter survival compared with patients with nonsense/frameshift mutations (P = .03). Our results suggest that AML1 mutations and deletion of genes on chromosome arm 7q cooperate in leukemogenesis and predispose to leukemic transformation. (C) 2004 by The American.