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, approximately 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.
Hasan
Syed Khizer
SK
Department of Biopathology, University of 'Rome Tor Vergata', Rome, Italy. syedk.hasan@uniroma2.it
Ottone
Tiziana
T
Schlenk
Richard F
RF
Xiao
Yuanyuan
Y
Wiemels
Joseph L
JL
Mitra
Maria Enza
ME
Bernasconi
Paolo
P
Di Raimondo
Francesco
F
Stanghellini
Maria Teresa Lupo
MT
Marco
Pepa
P
Mays
Ashley N
AN
Döhner
Hartmut
H
Sanz
Miguel A
MA
Amadori
Sergio
S
Grimwade
David
D
Lo-Coco
Francesco
F
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D056905:Chromosome Breakpoints; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000235:genetics*; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D008942:Mitoxantrone