Evidence for direct involvement of epirubicin in the formation of chromosomal translocations in t(15;17) therapy-related acute promyelocytic leukemia

Ashley N. Mays, Neil Osheroff, Yuanyuan Xiao, Joseph L. Wiemels, Carolyn A. Felix, Jo Ann W Byl, Kandeepan Saravanamuttu, Andrew Peniket, Robert Corser, Cherry Chang, Christine Hoyle, Anne N. Parker, Syed K. Hasan, Francesco Lo-Coco, Ellen Solomon, David Grimwade

Research output: Contribution to journalArticlepeer-review

Abstract

Therapy-related acute promyelocytic leukemia (t-APL) with t(15;17)(q22;q21) involving the PML and RARA genes is associated with exposure to agents targeting topoisomerase II (topoII), particularly mitoxantrone and epirubicin. We previously have shown that mitoxantrone preferentially induces topoII-mediated DNA damage in a "hotspot region" within PML intron 6. To investigate mechanisms underlying epirubicin-associated t-APL, t(15; 17) genomic breakpoints were characterized in 6 cases with prior breast cancer. Significant breakpoint clustering was observed in PML and RARA loci (P = .009 and P = .017, respectively), with PML breakpoints lying outside the mitoxantrone-associated hotspot region. Recurrent breakpoints identified in the PML and RARA loci in epirubicin-related t-APL were shown to be preferential sites of topoII-induced DNA damage, enhanced by epirubicin. Although site preferences for DNA damage differed between mitoxantrone and epirubicin, the observation that particular regions of the PML and RARA loci are susceptible to these agents may underlie their respective propensities to induce t-APL.

Original languageEnglish
Pages (from-to)326-330
Number of pages5
JournalBlood
Volume115
Issue number2
DOIs
Publication statusPublished - Jan 14 2010

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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