ANALYSIS OF THE JOINING SEQUENCES OF THE T(15-17) TRANSLOCATION IN HUMAN ACUTE PROMYELOCYTIC LEUKEMIA - SEQUENCE NONSPECIFIC RECOMBINATION BETWEEN THE PML AND RARA GENES WITHIN IDENTICAL SHORT STRETCHES

Molecular analysis of the t(15;17) translocation in 70 patients with a cute promyelocytic leukemia (APL) confirmed that the breakpoints of ch romosome 15 were located in two regions of the promyelocytic leukemia (PML) gene, mainly introns 3 and 6, whereas the breakpoints of chromos ome 17 were consistently in intron 2 of the retinoic acid receptor alp ha (RARA) gene. To study the reason for the clustering of the breakpoi nts and the underlying mechanism of the chromosomal translocation, we characterized the joining sequences of der(15) and der(17) by polymera se chain reaction in samples from eight patients with APC. There was n o cluster of the breakpoints within the introns, and no consensus sequ ence-motif was found around them. One Or nine extra nucleotides were i nserted into two joining sites. There were identical stretches one to seven nucleotides between the PML and RARA genes in the majority of th e joining sequences. These data provide a potential model of the t(15; 17) translocation: random DNA double strand cleavage, modification of DNA ends by enzymes including terminal deoxynucleotidyl transferase, a nd single strand base-pairing within identical short stretches. Furthe rmore, APL develops only when the PML and RARA genes are rearranged wi thin restricted genomic regions and a functional PML-RARA chimeric pro duct is produced, and this might lead to a clustering of the breakpoin ts. (C) 1995 Wiley-Liss, Inc.