6533b826fe1ef96bd1285192
RESEARCH PRODUCT
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
Yuanyuan XiaoDavid GrimwadeMaria Teresa Lupo StanghelliniPepa MarcoPaolo BernasconiAshley N. MaysSyed Khizer HasanRichard F. SchlenkFrancesco Di RaimondoHartmut DöhnerJoseph L. WiemelsMiguel A. SanzMaria Enza MitraTiziana OttoneFrancesco Lo-cocoSergio Amadorisubject
MaleCancer ResearchReceptors Retinoic AcidRetinoic AcidMessengerPromyelocytic Leukemia ProteinTranslocation GeneticChromosome BreakpointsLeukemia Promyelocytic Acuteimmune system diseasesReceptorsPromyelocyticGeneticsLeukemiabiologyReverse Transcriptase Polymerase Chain ReactionRetinoic Acid Receptor alphaNuclear ProteinsDNA NeoplasmMiddle AgedFemaleHumanAdultAcute promyelocytic leukemiaChromosome BreakpointsTranslocationAntineoplastic AgentsAcuteChromosomesYoung AdultPromyelocytic leukemia proteinGeneticGeneticsmedicineConsensus sequenceHumansRNA MessengerReceptors Retinoic Acid; Male; Young Adult; Middle Aged; Chromosome Breakpoints; Female; Chromosomes Human Pair 17; Tumor Suppressor Proteins; Humans; DNA Neoplasm; Translocation Genetic; Leukemia Promyelocytic Acute; Antineoplastic Agents; Nuclear Proteins; RNA Messenger; Mitoxantrone; Reverse Transcriptase Polymerase Chain Reaction; Chromosomes Human Pair 15; Transcription Factors; Aged; AdultneoplasmsAgedChromosomes Human Pair 15Pair 17Tumor Suppressor ProteinsTopoisomeraseBreakpointPair 15DNAmedicine.diseaseRetinoic acid receptor alphabiology.proteinNeoplasmRNAHuman genomeMitoxantroneSettore MED/15 - Malattie del SangueChromosomes Human Pair 17Transcription Factorsdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2010-06-15 | Genes, Chromosomes and Cancer |