IDENTIFICATION AND CHARACTERIZATION OF THE ARP1 GENE, A TARGET FOR THE HUMAN ACUTE-LEUKEMIA ALL1 GENE

ALL1, the human homologue of Drosophila trithorax, is directly involve d in human acute leukemias associated with abnormalities at 11q23. Usi ng the differential display method, we isolated a gene that is down-re gulated in All1 double knockout mouse embryonic stem (ES) cells. The g ene, designated ARP1 (also termed RIEG, Pxt2, or Otlx2), is a member o f a family of homeotic genes containing a short motif shared with seve ral homeobox genes. Using a bacterially synthesized All1 polypeptide e ncompassing the AT-hook motifs, we identified a 0.5-kb ARP1 DNA fragme nt that preferentially bound to the polypeptide. Within this DNA, a re gion of approximate to 100 bp was protected by the polypeptide from di gestion with ExoIII and DNase I. Whole-mount in situ hybridization to early mouse embryos of 9.5-10.5 days indicated a complex pattern of Ar p1 expression spatially overlapping with the expression of All1. Altho ugh the ARP1 gene is expressed strongly in bone marrow cells, no trans cripts were detected in six leukemia cell lines with 11q23 translocati ons. These results suggest that ARP1 is up-regulated by the All1 prote in, possibly through direct interaction with an upstream DNA sequence of the former. The results are also consistent with the suggestion tha t ALL1 chimeric proteins resulting from 11q23 abnormalities act in a d ominant negative fashion.