Architecture and anatomy of the genomic locus encoding the human leukemia-associated transcription factor RUNX1/AML1

The RUNX1 gene on human chromosome 21q22.12 belongs to the 'runt domain' ge ne family of transcription Factors (also known as AML/CBFA/PEBP2 alpha). RU NX1 is a key regulator of hematopoiesis and a frequent target of leukemia a ssociated chromosomal translocations. Here we present a detailed analysis o f the RUNX1 locus based on its complete genomic sequence. RUNX1 spans 260 k b and its expression is regulated through two distinct promoter regions, th at are 160 kb apart. A very large CpG island complex marks the proximal pro moter (promoter-2), and an additional CpG island is located at the 3' end o f the gene. Hitherto, 12 different alternatively spliced RUNX1 cDNAs have b een identified. Genomic sequence analysis of intron/exon boundaries of thes e cDNAs has shown that all consist of properly spliced authentic coding reg ions. This indicates that the large repertoire of RUNX1 proteins, ranging i n size between 20-52 kDa, are generated through usage of alternatively spli ced exons some of which contain in frame stop codons. The gene's introns ar e largely depleted of repetitive sequences, especially of the LINE1 family. The RUNX1 locus marks the transition from a similar to1 Mb of gene-poor re gion containing only pseudogenes, to a gene-rich region containing several functional genes. A search for RUNX1 sequences that may be involved in the high frequency of chromosomal translocations revealed that a 555 bp long se gment originating in chromosome 11 FLI1 gene was transposed into RUNX1 intr on 3.1. This intron harbors the t(8;21) and t(3;21) chromosomal breakpoints involved in acute myeloid leukemia. Interestingly, the FLI1 homologous seq uence contains a breakpoint of the t(11;22) translocation associated with E wing's tumors, and may have a similar function in RUNX1. (C) 2001 Elsevier Science B.V. All rights: reserved.