Identification of a potential "Hotspot" DNA region in the RUNXI gene targeted by mitoxantrone in therapy-related acute myeloid leukemia with t(16;21) translocation

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

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Abstract

The translocation t(l6;2l) involving RUNXI (AMLI) and resulting in the RUNXI-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(l6;2l) 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 RUNXI and CBFA2T3 (ETO2) breakpoints in introns 5 and 3, respectively. Sequencing of the cDNA with specific primers showed the presence of the expected RUNXI-CBFA2T3 fusion transcript in leukemic cells. The RUNXI 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.

Original languageEnglish
Pages (from-to)213-221
Number of pages9
JournalGenes Chromosomes and Cancer
Volume48
Issue number3
DOIs
Publication statusPublished - Mar 2009

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ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

Ottone, T., Hasan, S. K., Montefusco, E., Curzi, P., Mays, A. N., Chessa, L., Ferrari, A., Conte, E., Noguera, N. I., Lavorgna, S., Ammatuna, E., Divona, M., Bovetti, K., Amadori, S., Grimwade, D., & Lo-Coco, F. (2009). Identification of a potential "Hotspot" DNA region in the RUNXI gene targeted by mitoxantrone in therapy-related acute myeloid leukemia with t(16;21) translocation. Genes Chromosomes and Cancer, 48(3), 213-221. https://doi.org/10.1002/gcc.20633