Translocation breakpoint of acute promyelocytic leukemia lies within the retinoic acid receptor alpha locus

Acute promyelocytic leukemias (APLs) are characterized by a reciprocal balanced translocation that involves chromosomes 15 and 17 [t(15;17)]. We report the isolation and characterization of one of the two reciprocal break sites and demonstrate that the chromosome 17 breakpoint lies within the retinoic acid receptor-alpha locus. Nucleotide sequencing of the 15;17 cross-over junction on 15q+ showed that the retinoic acid receptor-alpha gene is truncated within its first intron, 370 base pairs upstream from the splicing donor site of exon II. Such a recombination would be expected to generate abnormal RAR-alpha mRNA and protein. Southern blot analysis of a number of APLs with chromosome 15- and 17-derived DNA probes revealed similar 15;17 recombinations in the majority of other APLs. Our data are strong evidence that the retinoic acid receptor-alpha gene plays a crucial role in the leukemogenesis of APL