Clonal haemopoiesis may occur after conventional chemotherapy and is associated with accelerated telomere shortening and defects in the NQO1 pathway; possible mechanisms leading to an increased risk of t-AML/MDS
Clonal haemopoiesis may occur after conventional chemotherapy and is associated with accelerated telomere shortening and defects in the NQO1 pathway; possible mechanisms leading to an increased risk of t-AML/MDS
复制标题
DOI：
10.1111/j.1365-2141.2004.05006.x
复制
发表时间：
2004-07-01
影响因子：
6.5
通讯作者：
Byrne, J
中科院分区：
文献类型：
--
作者：
Fern, L;Pallis, M;Byrne, J
与治疗相关的急性髓系白血病/骨髓增生异常综合征(t-AML/MDS)的分子发病机制尚不清楚。然而，克隆性造血可能在干细胞移植后发展，并先于t-AML/MDS的发展。此外，复制应激或氧化损伤可能导致端粒加速缩短，导致基因组不稳定，编码NADPH-QO1基因的失活多态性在t-AML患者中更常见。我们研究了146例接受常规化疗的非髓系恶性肿瘤患者的克隆性造血、端粒长度和NQO1状态。98例患者中有8例(8%)表现为克隆性造血。化疗后患者(n=52)的端粒长度较对照组(n=42)缩短(P<；0.001)，尤其是克隆性造血患者(P<；0.002)。NQO1-187Ser多态的对照组(n=12)有端粒缩短的趋势，而化疗暴露的NQO1-187Ser等位基因多态的患者(n=29)端粒显著缩短(P<；0.001)。此外，携带NQO1-187Ser，多态的化疗患者比携带野生型NQO1的患者更容易发生克隆性造血(优势比=7；1.16-42.6)。我们得出结论，在常规化疗后，可能会发生向克隆性造血的转变，并导致端粒加速缩短。具有NQO1-187Ser多态的患者发生克隆性造血和端粒缩短的风险增加，这可能是NQO1-187Ser缺失者易患t-AML的部分原因。
The molecular pathogenesis of therapy-related acute myeloid leukaemia/myelodysplastic syndrome (t-AML/MDS) remains uncertain. However, clonal haemopoiesis may develop following stem cell transplantation and precede the development of t-AML/MDS. Moreover, accelerated telomere shortening may be induced by replicative stress or oxidative damage, leading to genomic instability, and inactivating polymorphisms of the gene encoding NADPH-quinone oxidoreductase (NQO1) are more frequently observed in patients with t-AML. We studied clonal haemopoiesis, telomere length and NQO1 status in 146 patients receiving conventional chemotherapy for non-myeloid malignancies. Clonal haemopoiesis was demonstrated in eight of 98 (8%) patients. Telomere length was reduced in patients following chemotherapy (n = 52) compared with controls (n = 42) (P < 0.001), particularly in those with clonal haemopoiesis (P < 0.002). Whilst there was a trend towards telomere shortening in control subjects polymorphic for NQO1-187Ser (n = 12), chemotherapy-exposed patients polymorphic for the NQO1-187Ser allele (n = 29) had significantly shorter telomeres (P < 0.001). Furthermore, chemotherapy-treated patients with the NQO1-187Ser, polymorphism were more likely to develop clonal haemopoiesis than patients with wild type NQO1 (odds ratio = 7; 1.16-42.6). We conclude that a switch to clonal haemopoiesis may occur after conventional chemotherapy and lead to accelerated telomere shortening. Patients with the NQO1-187Ser polymorphism have an increased risk of developing both clonal haemopoiesis and telomere shortening, which may partly explain the predisposition to t-AML in NQO1-187Ser null individuals.