title: Identification of a potential "hotspot" DNA region in the RUNX1 gene targeted by mitoxantrone in therapy-related acute myeloid leukemia with t(16;21) translocation.
abstract: The translocation t(16;21) involving RUNX1 (AML1) and resulting in the RUNX1-CBFA2T3 fusion is a rare but recurrent abnormality mostly found in therapy-related acute myeloid leukemia (t-AML) associated with agents targeting topoisomerase II (topo II). We characterized, at the genomic level, the t(16;21) translocation in a patient who developed t-AML after treatment of multiple sclerosis with mitoxantrone (MTZ). Long template nested PCR of genomic DNA followed by direct sequencing enabled the localization of RUNX1 and CBFA2T3 (ETO2) breakpoints in introns 5 and 3, respectively. Sequencing of the cDNA with specific primers showed the presence of the expected RUNX1-CBFA2T3 fusion transcript in leukemic cells. The RUNX1 intron 5 breakpoint was located at nucleotide position 24,785. This region contained an ATGCCCCAG nucleotide sequence showing approximately 90% homology to a "hotspot" DNA region ATGCCCTAG present in intron 6 of PML previously identified in therapy-related acute promyelocytic leukemia cases arising following treatment with MTZ. This study suggests a wider distribution in the human genome, and particularly at genes involved in chromosome translocations observed in t-AML, of DNA regions (hotspot) targeted by specific topo II drugs.
authors.affiliation: Dipartimento di Biopatologia e Diagnostica per Immagini, University Tor Vergata, Rome, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Ottone
authors.forename: Syed Khizer
authors.initials: SK
authors.lastname: Hasan
authors.forename: Enrico
authors.initials: E
authors.lastname: Montefusco
authors.forename: Paola
authors.initials: P
authors.lastname: Curzi
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Mays
authors.forename: Luciana
authors.initials: L
authors.lastname: Chessa
authors.forename: Antonella
authors.initials: A
authors.lastname: Ferrari
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Conte
authors.forename: Nelida Inés
authors.initials: NI
authors.lastname: Noguera
authors.forename: Serena
authors.initials: S
authors.lastname: Lavorgna
authors.forename: Emanuele
authors.initials: E
authors.lastname: Ammatuna
authors.forename: Mariadomenica
authors.initials: M
authors.lastname: Divona
authors.forename: Katia
authors.initials: K
authors.lastname: Bovetti
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.forename: David
authors.initials: D
authors.lastname: Grimwade
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo-Coco
mesh_terms: D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D020732:Cytogenetic Analysis; D030541:Databases, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000009:adverse effects* / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000150:complications / Q000188:drug therapy; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D059005:Topoisomerase II Inhibitors; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C115744:CBFA2T3 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D010750:Phosphoproteins; C493728:RUNX1 protein, human; D012097:Repressor Proteins; D059005:Topoisomerase II Inhibitors; D025521:Tumor Suppressor Proteins; D008942:Mitoxantrone