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

• DOI: 10.1002/gcc.20633
• Publication Date: 2008-11-20T20:04:30Z
• Authors: 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
• Keywords: Mitoxantrone; RUNX1

Abstract The translocation t(16;21) involving RUNX1 ( AML1 ) and resulting in the RUNX1‐CBFA2T3 fusion is a rare but recurrent abnormality mostly found therapy‐related acute myeloid leukemia (t‐AML) associated with agents targeting topoisomerase II (topo II). We characterized, at genomic level, patient who developed t‐AML after treatment of multiple sclerosis mitoxantrone (MTZ). Long template nested PCR DNA followed by direct sequencing enabled localization CBFA2T3 ETO2 breakpoints introns 5 3, respectively. Sequencing cDNA specific primers showed presence expected transcript leukemic cells. intron breakpoint was located nucleotide position 24,785. This region contained an ATGCCCCAG sequence showing ∼90% homology to “hotspot” ATGCCCTAG present 6 PML previously identified promyelocytic cases arising following MTZ. study suggests wider distribution human genome, particularly genes involved chromosome translocations observed t‐AML, regions (hotspot) targeted topo drugs. © 2008 Wiley‐Liss, Inc.