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
✍ Scribed by Tiziana Ottone; Syed Khizer Hasan; Enrico Montefusco; Paola Curzi; Ashley N. Mays; Luciana Chessa; Antonella Ferrari; Esmeralda Conte; Nelida Inés Noguera; Serena Lavorgna; Emanuele Ammatuna; Mariadomenica Divona; Katia Bovetti; Sergio Amadori; David Grimwade; Francesco Lo-Coco
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 253 KB
- Volume
- 48
- Category
- Article
- ISSN
- 1045-2257
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✦ Synopsis
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 ∼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.