SEQUENCE AND ANALYSIS OF THE HUMAN ABL GENE, THE BCR GENE, AND REGIONS INVOLVED IN THE PHILADELPHIA CHROMOSOMAL TRANSLOCATION

The complete human BCR gene (152-141 nt) on chromosome 22 and greater than 80% of the human ABL gene (179-512 nt) on chromosome 9 have been sequenced from mapped cosmid and plasmid clones via a shotgun strategy . Because these two chromosomes are translocated with breakpoints with in the BCR and ABL genes in Philadelphia chromosome-positive leukemias , knowledge of these sequences also might provide insight into the val idity of various theories of chromosomal rearrangements. Comparison of these genes with their cDNA sequences reveal the positions of 23 BCR exons and putative alternative BCR first and second exons, as well as the common ABL exons 2-11, respectively. Additionally, these regions i nclude the alternative ABL first exons 1b and 1a, a new gene 5' to the first ABL exon, and an open reading frame with homology to an EST wit hin the BCR fourth intron. Further analysis reveals an Alu homology of 38.83 and 39.35% for the BCR and ABL genes, respectively, with other repeat elements present to a lesser extent. Four new Philadelphia chro mosome translocation breakpoints from chronic myelogenous leukemia pat ients also were sequenced, and the positions of these and several othe r previously sequenced breakpoints now have been mapped precisely, alt hough no consistent breakpoint features immediately were apparent. Com parative analysis of genomic sequences encompassing the murine homolog ues to the human ABL exons 1b and 1a, as well as regions encompassing the ABL exons 2 and 3, reveals that although there is a high degree of homology in their corresponding exons and promoter regions, these two vertebrate species show a striking lack of homology outside these reg ions. (C) 1995 Academic Press, Inc.