Domer P H, Fakharzadeh S S, Chen C S, Jockel J, Johansen L, Silverman G A, Kersey J H, Korsmeyer S J
Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110.
Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7884-8. doi: 10.1073/pnas.90.16.7884.
A chromosomal translocation, t(4;11)-(q21;q23), is associated with an aggressive mixed-lineage leukemia. A yeast artificial chromosome was used to clone the chromosomal breakpoint of this translocation in the RS4;11 cell line. The breakpoint sequences revealed an inverted repeat bordered by a consensus site for topoisomerase II binding and cleavage as well as chi-like elements. The der(11) chromosome encodes a fusion RNA and predicted chimeric protein between the 11q23 gene MLL and a 4q21 gene designated AF4. The sequence of the complete open reading frame for this fusion transcript reveals the MLL protein to have homology with DNA methyltransferase, the Drosophila trithorax gene product, and the "AT-hook" motif of high-mobility-group proteins. An alternative splice that deletes the AT-hook region of MLL was identified. AF4 is a serine- and proline-rich putative transcription factor with a glutamine-rich carboxyl terminus. The composition of the complete MLL-AF4 fusion product argues that it may act through either a gain-of-function or a dominant negative mechanism in leukemogenesis.
一种染色体易位，t(4;11)-(q21;q23)，与侵袭性混合谱系白血病相关。利用酵母人工染色体克隆了RS4;11细胞系中这种易位的染色体断点。断点序列显示出一个反向重复序列，其边界为拓扑异构酶II结合与切割的共有位点以及类chi元件。der(11)染色体编码一种融合RNA以及预测的11q23基因MLL与一个名为AF4的4q21基因之间的嵌合蛋白。该融合转录本完整开放阅读框的序列显示，MLL蛋白与DNA甲基转移酶、果蝇三体胸基因产物以及高迁移率族蛋白的“AT钩”基序具有同源性。鉴定出一种缺失MLL的AT钩区域的可变剪接。AF4是一种富含丝氨酸和脯氨酸的假定转录因子，其羧基末端富含谷氨酰胺。完整的MLL-AF4融合产物的组成表明，它可能在白血病发生过程中通过功能获得或显性负性机制发挥作用。
