Stephenson J, Czepulkowski B, Hirst W, Mufti G J
Department of Haematological Medicine, King's College School of Medicine and Dentistry, London, UK.
Leuk Res. 1996 Mar;20(3):235-41. doi: 10.1016/0145-2126(95)00146-8.
The genes for acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) are located within regions subject to non-random chromosomal abnormalities in the myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Acetylcholinesterase is mapped to 7q22, within the critical deleted region presumed to contain a myeloid specific tumour suppressor gene. Butyrylcholinesterase is mapped to 3q26: abnormalities at this region are associated with sub-types of MDS and AML with thrombocytopenia, or with increased platelet counts. Both ACHE and BCHE have been implicated as playing a role in megakaryopoiesis and thrombopoiesis, and these genes have been observed to be co-amplified in acute myeloid leukaemia. Recent findings suggest a more significant role for the ACHE gene in haemopoiesis by regulating multipotent stem cell proliferation, and apoptosis in cells undergoing erythroid and myeloid differentiation. This led us to investigate gene copy-number alterations at these genes in MDS and AML. Samples were screened by slot-blot hybridization, and if changes were observed, by Southern blotting. A total of 42 samples from 31 de novo AML patients, 10 samples from eight cases of post-MDS AML and 85 samples from 67 MDS patients were analysed with probes for ACHE, BCHE, c-MYC, MDR-1 and globin control. Changes in ACHE and/or BCHE were observed in 9/31 de novo AML patients, and in 7/67 MDS patients: 1/37 cases of refractory anaemia (RA), 1/10 cases of refractory anaemia with excess blasts (RAEB) and 5/20 chronic myelomonocytic leukaemia (CMML) patients. The amplification events observed generated copy numbers no greater than 10, showed normal restriction patterns and had no clear correlation with megakaryopoiesis or thrombopoiesis. Loss of signal at the ACHE locus was observed: haploid signal intensity was seen in seven samples: one RA with thrombocytopenia, three CMML, one AML-M5a (no karyotypic abnormalities of chromosome 7), one AML-M4 (monosomy 7), and one case of AML-M7 (karyotype unknown). Homozygous deletion was observed at relapse of an additional patient with AML-M4. These data reinforce the possibility that ACHE may play a role as a myeloid tumour suppressor gene.
乙酰胆碱酯酶（ACHE）基因和丁酰胆碱酯酶（BCHE）基因位于骨髓增生异常综合征（MDS）和急性髓系白血病（AML）中存在非随机染色体异常的区域。乙酰胆碱酯酶定位于7q22，在推测含有髓系特异性肿瘤抑制基因的关键缺失区域内。丁酰胆碱酯酶定位于3q26：该区域的异常与伴有血小板减少症或血小板计数增加的MDS和AML亚型相关。ACHE和BCHE均被认为在巨核细胞生成和血小板生成中起作用，并且在急性髓系白血病中观察到这些基因共扩增。最近的研究结果表明，ACHE基因通过调节多能干细胞增殖以及红细胞和髓细胞分化过程中细胞的凋亡，在造血过程中发挥更重要的作用。这促使我们研究MDS和AML中这些基因的基因拷贝数改变。通过狭缝印迹杂交对样本进行筛选，如果观察到变化，则进行Southern印迹分析。用ACHE、BCHE、c-MYC、MDR-1和珠蛋白对照探针分析了31例初发AML患者的42个样本、8例MDS后AML患者的10个样本以及67例MDS患者的85个样本。在9/31例初发AML患者和7/67例MDS患者中观察到ACHE和/或BCHE的变化：1/37例难治性贫血（RA）、1/10例伴有过多原始细胞的难治性贫血（RAEB）和5/20例慢性粒单核细胞白血病（CMML）患者。观察到的扩增事件产生的拷贝数不超过10，显示出正常的限制性图谱，并且与巨核细胞生成或血小板生成无明显相关性。在ACHE基因座观察到信号缺失：在7个样本中观察到单倍体信号强度：1例伴有血小板减少症的RA、3例CMML、1例AML-M5a（7号染色体无核型异常）、1例AML-M4（7号染色体单体）和1例AML-M7（核型未知）。在另一例AML-M4患者复发时观察到纯合缺失。这些数据强化了ACHE可能作为髓系肿瘤抑制基因发挥作用的可能性。
