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.
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.
Ottone
Tiziana
T
Dipartimento di Biopatologia e Diagnostica per Immagini, University Tor Vergata, Rome, Italy.
Hasan
Syed Khizer
SK
Montefusco
Enrico
E
Curzi
Paola
P
Mays
Ashley N
AN
Chessa
Luciana
L
Ferrari
Antonella
A
Conte
Esmeralda
E
Noguera
Nelida Inés
NI
Lavorgna
Serena
S
Ammatuna
Emanuele
E
Divona
Mariadomenica
M
Bovetti
Katia
K
Amadori
Sergio
S
Grimwade
David
D
Lo-Coco
Francesco
F
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
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