急性白血病相关融合基因MLL-EEN研究进展

Review on acute leukemia fusion gene MLL-EEN

对白血病中大量重现的细胞遗传学异常分子水平研究揭示,遗传学异常在白血病发生中起重要作用。11q23易位是白血病中常见的细胞遗传学异常,含11q23基因重排的急性髓性白血病(acute myeloid leukemia,AML)预后不良。混合系白血病基因(mixed linage leu-kemia gene,MLL)基因定位于11q23,是果蝇三胸基因的人类同系物。目前与MLL发生融合的伙伴基因已超过40个,分布于约60个位点。EEN最初发现于1例t(11;19)(q23;p13)易位的AML患者,是在19p13位点发现的第3个MLL伙伴基因。MLL外显子6的N末端连接到EEN的16个氨基酸后的C末端,形成的融合蛋白包括MLL的AT钩和甲基转移酶同源区,以及EEN的α螺旋区和SH3结构域。MLL-EEN在白血病中的分子机制可能通过磷酸肌醇途径、调控HOX基因、抑制EBP相关的Ras活动、与其他基因的交互作用以及联合致病机制而起作用。目前对MLL-EEN的研究正逐渐深入,有效治疗白血病依赖于对白血病相关基因异常机制全面深入地研究。

Molecular study of many recurring cytogenetic abnormalities has revealed genes that may be involved in leukemogenesis. 11q23 translocation is one of the frequently reported abnormalities. Prognosis of AML with 11q23 rearrangements is poor. The human homologue of the Drosophila trithorax gene, MLL is located on chromosome 11q23, which is involved in translocations with over 40 different chromosome partners, and MLL is translocated to approximately 60 differ ent chromosomal loci. First identified from an AML patient with t（11 ;19）（q23;p13） translocations, EEN is the third gene characterized on chromosome 19p13 that fuses to MLL in hu- man leukemia. As exon 6 of MLL is fused to EEN at amino acid 16, the fusion product contains the AT hooks and methyltransferase homology regions of MLL, joined to the α-helical region and SH3 domain of EEN. The leukemogenesis mechanisms of MLL-EEN may be related to phosphoinositol pathway, HOX gene regulation, EBP related Ras activities suppression, interactions with other fusion partners or a synergic pathogenic mechanism. The effectiveness of treatment to this malicious disease depends on what depth we understand the nature of these mutations.