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
Tiziana Ottone
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorSyed Khizer Hasan
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorEnrico Montefusco
Azienda Ospedaliera Sant'Andrea, University “La Sapienza,” Rome, Italy
Search for more papers by this authorPaola Curzi
Dipartimento di Medicina di Laboratorio, Policlinico Tor Vergata, Rome, Italy
Search for more papers by this authorAshley N. Mays
Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK
Search for more papers by this authorLuciana Chessa
Azienda Ospedaliera Sant'Andrea, University “La Sapienza,” Rome, Italy
Search for more papers by this authorAntonella Ferrari
Azienda Ospedaliera Sant'Andrea, University “La Sapienza,” Rome, Italy
Search for more papers by this authorEsmeralda Conte
Azienda Ospedaliera Sant'Andrea, University “La Sapienza,” Rome, Italy
Search for more papers by this authorNelida Inés Noguera
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorSerena Lavorgna
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorEmanuele Ammatuna
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorMariadomenica Divona
Dipartimento di Medicina di Laboratorio, Policlinico Tor Vergata, Rome, Italy
Search for more papers by this authorKatia Bovetti
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorSergio Amadori
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorDavid Grimwade
Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK
Search for more papers by this authorCorresponding Author
Francesco Lo-Coco
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Dipartimento di Medicina di Laboratorio, Policlinico Tor Vergata, Rome, Italy
Department of Biopathology, University Tor Vergata, Via Montpellier 1, 00133 Roma, ItalySearch for more papers by this authorTiziana Ottone
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorSyed Khizer Hasan
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorEnrico Montefusco
Azienda Ospedaliera Sant'Andrea, University “La Sapienza,” Rome, Italy
Search for more papers by this authorPaola Curzi
Dipartimento di Medicina di Laboratorio, Policlinico Tor Vergata, Rome, Italy
Search for more papers by this authorAshley N. Mays
Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK
Search for more papers by this authorLuciana Chessa
Azienda Ospedaliera Sant'Andrea, University “La Sapienza,” Rome, Italy
Search for more papers by this authorAntonella Ferrari
Azienda Ospedaliera Sant'Andrea, University “La Sapienza,” Rome, Italy
Search for more papers by this authorEsmeralda Conte
Azienda Ospedaliera Sant'Andrea, University “La Sapienza,” Rome, Italy
Search for more papers by this authorNelida Inés Noguera
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorSerena Lavorgna
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorEmanuele Ammatuna
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorMariadomenica Divona
Dipartimento di Medicina di Laboratorio, Policlinico Tor Vergata, Rome, Italy
Search for more papers by this authorKatia Bovetti
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorSergio Amadori
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Search for more papers by this authorDavid Grimwade
Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK
Search for more papers by this authorCorresponding Author
Francesco Lo-Coco
Dipartimento di Biopatologia e Diagnostica per Immagini, University “Tor Vergata,” Rome, Italy
Dipartimento di Medicina di Laboratorio, Policlinico Tor Vergata, Rome, Italy
Department of Biopathology, University Tor Vergata, Via Montpellier 1, 00133 Roma, ItalySearch for more papers by this authorAbstract
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 ∼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. © 2008 Wiley-Liss, Inc.
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