Sacchi N, Nisson P E, Watkins P C, Faustinella F, Wijsman J, Hagemeijer A
Department of Biology and Genetics, School of Medicine, University of Milan, Italy.
Genes Chromosomes Cancer. 1994 Dec;11(4):226-36. doi: 10.1002/gcc.2870110405.
The t(3;21)(q26;q22) is associated with chronic myelogenous leukemia in blast crisis (CML-BC), leukemia evolving from (therapy-related) myelodysplasia, and with leukemia following other hematopoietic proliferative diseases. Molecular cytogenetic analysis and cloning of a few t(3;21) cases indicate that the breakpoints are quite heterogeneous even within a specific clinical phenotype. Interestingly some of the (3;21) breakpoints involve the AML1 gene previously found rearranged in the t(8;21) associated with acute myelogenous leukemia. AML1 is related to the Drosophila gene runt and is the human counterpart of the gene for the alpha subunit of the nuclear polyoma enhancer binding protein (PEBP2) also known as the core binding factor (CBF). In the t(3;21) AML1 was found rearranged with EAP, a gene on chromosome 3 encoding a small ribosomal protein, as well as with EV11, another gene on chromosome 3. Here we report our study of six cases of t(3;21). By using fluorescence in situ hybridization (FISH) analysis and AML1 probes we could conclude that at least in two CML-BC cases the breakpoint occurred in the AML1 intron that is disrupted by the t(8;21). An AML1/EAP fusion transcript, different from the one described in a therapy-related myelodysplasia, was detected in both CML-BC cases. This transcript is expected to result in a predicted protein containing the AML1 nuclear binding domain with an attached stretch of 17 amino acids unrelated to the EAP small ribosomal protein. In the other t(3;21) patients we could not detect an AML1/EAP transcript or an AML1/EV11 transcript. This result suggests heterogeneity of the t(3;21) at the molecular level. The AML1 chimeric transcripts identified so far, both in the t(3;21) and in the t(8;21), diverge from the normal transcripts either after exon 5 or exon 6. Here we show that in normal AML1 transcripts different splicing events are seen to occur after AML1 exon 5 as well as exon 6.
t(3;21)(q26;q22)与急变期慢性粒细胞白血病（CML-BC）、由（治疗相关）骨髓增生异常综合征演变而来的白血病以及其他造血增殖性疾病后的白血病相关。对少数t(3;21)病例的分子细胞遗传学分析和克隆表明，即使在特定临床表型内，断点也相当异质性。有趣的是，一些t(3;21)断点涉及先前在与急性髓性白血病相关的t(8;21)中发现重排的AML1基因。AML1与果蝇的runt基因相关，是核多瘤病毒增强子结合蛋白（PEBP2）α亚基基因的人类对应物，也称为核心结合因子（CBF）。在t(3;21)中，发现AML1与EAP重排，EAP是3号染色体上编码一种小核糖体蛋白的基因，还与3号染色体上的另一个基因EV11重排。在此我们报告对6例t(3;21)病例的研究。通过使用荧光原位杂交（FISH）分析和AML1探针，我们可以得出结论，至少在2例CML-BC病例中，断点发生在被t(8;21)破坏的AML1内含子中。在2例CML-BC病例中均检测到一种与治疗相关的骨髓增生异常综合征中描述的不同的AML1/EAP融合转录本。预计该转录本会产生一种预测的蛋白质，其包含AML1核结合结构域以及一段与EAP小核糖体蛋白无关的17个氨基酸的延伸序列。在其他t(3;21)患者中，我们未检测到AML1/EAP转录本或AML1/EV11转录本。这一结果表明t(3;21)在分子水平上具有异质性。到目前为止，在t(3;21)和t(8;21)中鉴定出的AML1嵌合转录本，在第5外显子或第6外显子之后与正常转录本不同。在此我们表明，在正常AML1转录本中，在AML1第5外显子以及第6外显子之后会出现不同的剪接事件。
