Roulston D, Espinosa R, Nucifora G, Larson R A, Le Beau M M, Rowley J D
Section of Hematology/Oncology, Department of Medicine, and the Cancer Research Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
Blood. 1998 Oct 15;92(8):2879-85.
CBFA2(AML1) has emerged as a gene critical in hematopoiesis; its protein product forms the DNA-binding subunit of the heterodimeric core-binding factor (CBF) that binds to the transcriptional regulatory regions of genes, some of which are active specifically in hematopoiesis. CBFA2 forms a fusion gene with ETO and MDS1/EVI1 in translocations in myeloid leukemia and with ETV6(TEL) in the t(12;21) common in childhood pre-B acute lymphoblastic leukemia. We have analyzed samples from 30 leukemia patients who had chromosome rearrangements involving 21q22 by using fluorescence in situ hybridization (FISH). Our analysis showed that 7 of them involved CBFA2 and new translocation partners. Two patients had a t(17;21)(q11.2;q22), whereas the other 5 had translocations involving 1p36, 5q13, 12q24, 14q22, or 15q22. Five of these novel breakpoints in CBFA2 occurred in intron 6; this same intron is involved in the t(3;21). One breakpoint mapped to the t(8;21) breakpoint region in intron 5, and 1 mapped 5' to that region. All 7 CBFA2 rearrangements resulted from balanced translocations. All 7 patients had myeloid disorders (acute myeloid leukemia or myelodysplastic syndrome); 2 were de novo and 5 had treatment histories that included topoisomerase II targeting agents. The association of therapy-related disorders with translocations involving CBFA2 was significant by Fisher's exact test (P < .003). These results provide further evidence that this region of CBFA2 is susceptible to breakage in cells exposed to topoisomerase II inhibitors.
核心结合因子α2（CBFA2，又称AML1）已成为造血过程中的关键基因；其蛋白质产物构成异二聚体核心结合因子（CBF）的DNA结合亚基，该因子可与基因的转录调控区域结合，其中一些基因在造血过程中具有特异性活性。在髓系白血病的易位中，CBFA2与ETO和MDS1/EVI1形成融合基因，在儿童前B急性淋巴细胞白血病常见的t(12;21)中与ETV6（TEL）形成融合基因。我们使用荧光原位杂交（FISH）分析了30例染色体重排涉及21q22的白血病患者的样本。我们的分析表明，其中7例涉及CBFA2和新的易位伙伴。2例患者发生t(17;21)(q11.2;q22)，而另外5例患者的易位涉及1p36、5q13、12q24、14q22或15q22。CBFA2中的5个新断点位于内含子6；t(3;21)也涉及该内含子。1个断点定位于内含子5中的t(8;21)断点区域，另1个断点位于该区域的5'端。所有7例CBFA2重排均由平衡易位导致。所有7例患者均患有髓系疾病（急性髓系白血病或骨髓增生异常综合征）；2例为初发，5例有包括拓扑异构酶II靶向药物的治疗史。通过Fisher精确检验，治疗相关疾病与涉及CBFA2的易位之间的关联具有显著性（P <.003）。这些结果进一步证明，在暴露于拓扑异构酶II抑制剂的细胞中，CBFA2的该区域易发生断裂。
