Bellido Mar, Aventín Anna, Lasa Adriana, Estivill Camino, Carnicer Maria J, Pons Cristina, Matías-Guiu Xavier, Bordes Ramón, Baiget Montserrat, Sierra Jorge, Nomdedéu Josep F
Laboratori d'Hematologia, Hospital de la Santa Creu i Sant Pau, Avda Sant Antoni M. Claret 167, 08025 Barcelona, Spain.
Haematologica. 2003 Sep;88(9):994-1001.
Chromosome translocations resulting in gene overexpression are commonly associated with lymphoid neoplasia. Enhancer elements of the immunoglobulin or T-cell receptor (TCR) loci are abnormally located in the vicinity of the entire coding sequences of genes which exert an influence on the normal maturation and differentiation program of lymphoid cells.
A patient who presented with a B-cell lineage acute lymphoblastic leukemia had a t(6;14)(p22;q32). Cytogenetic and molecular findings confirmed the involvement of IgH. Molecular cloning of the breakpoint revealed that this was located near the coding sequence of the Id4 gene, a helix-loop-helix (HLH) inhibitor protein. Alu-repeated sequences at the 6p22 end flanked a short stretch of 10 bases shared by the 6p22 and 14q32 ends, suggesting that a deletion or a looping-Alu mediated mispairing mechanism may lead to this chromosome translocation.
Northern blot and real-time polymerase chain reaction analyses showed that the Id4 mRNA was abnormally overexpressed in this case. Only the two smaller Id4 mRNA products were detected (1.6 and 1.1 kb). Immunohistochemical analysis of Id4 protein was also assayed in a series of hematologic malignancies. Marked overexpression was found in two cases of T-cell prolymphocytic leukemias and in four B-cell lineage acute lymphoblastic leukemia including one case with the t(8;14) and another case with a p53 mutation.
The Id4 gene may behave as an oncogene in some human leukemias, perhaps through its capacity to sequester specific B-cell transcription factors. A genetic recombination between Alu-repeated sequences may not be the exclusive mechanism of generating pathogenic chromosomal translocations.
导致基因过表达的染色体易位通常与淋巴样肿瘤相关。免疫球蛋白或T细胞受体（TCR）基因座的增强子元件异常定位在对淋巴样细胞正常成熟和分化程序产生影响的基因的整个编码序列附近。
一名表现为B细胞系急性淋巴细胞白血病的患者存在t(6;14)(p22;q32)。细胞遗传学和分子学结果证实了免疫球蛋白重链（IgH）的受累。断点的分子克隆显示其位于Id4基因的编码序列附近，Id4是一种螺旋-环-螺旋（HLH）抑制蛋白。6p22末端的Alu重复序列两侧是6p22和14q32末端共有的一小段10个碱基的序列，提示缺失或Alu介导的环化错配机制可能导致这种染色体易位。
Northern印迹和实时聚合酶链反应分析表明，该病例中Id4 mRNA异常过表达。仅检测到两种较小的Id4 mRNA产物（1.6和1.1 kb）。还对一系列血液系统恶性肿瘤进行了Id4蛋白的免疫组织化学分析。在两例T细胞幼淋巴细胞白血病和四例B细胞系急性淋巴细胞白血病中发现明显过表达，其中一例伴有t(8;14)，另一例伴有p53突变。
Id4基因在某些人类白血病中可能表现为癌基因，可能是通过其隔离特定B细胞转录因子的能力。Alu重复序列之间的基因重组可能不是产生致病性染色体易位的唯一机制。
