Analysis of t(15;17) chromosomal breakpoint sequences in therapy-related versus de novo acute promyelocytic leukemia: Association of DNA breaks with specific DNA motifs at PML and RARA loci

We compared genomic breakpoints at the PML and RARA loci in 23 patients with therapy‐related acute promyelocytic leukemia (t‐APL) and 25 de novo APL cases.Eighteen of 23 t‐APL cases received the topoisomerase II poison mitoxantrone for their primary disorder. DNA breaks were clustered in a previously reported 8 bp “hot spot” region of PML corresponding to a preferred site of mitoxantrone‐induced DNA topoisomerase II‐mediated cleavage in 39% of t‐APL occurring in patients exposed to this agent and in none of the cases arising de novo (P = 0.007). As to RARA breakpoints, clustering in a 3′ region of intron 2 (region B) was found in 65% of t‐APL and 28% of de novo APL patients, respectively. Scan statistics revealed significant clustering of RARA breakpoints in region B in t‐APL cases (P = 0.001) as compared to de novo APL (P = 1). Furthermore, ∼300 bp downstream of RARA region B contained a sequence highly homologous to a topoisomerase II consensus sequence. Biased distribution of DNA breakpoints at both PML and RARA loci suggest the existence of different pathogenetic mechanisms in t‐APL as compared with de novo APL. © 2010 Wiley‐Liss, Inc.