Molecular pathogenesis of secondary acute promyelocytic leukemia

Melanie Joannides, Ashley N. Mays, Anita R. Mistry, Syed Khizer Hasan, Andreas Reiter, Joseph L. Wiemels, Carolyn A. Felix, Francesco Lo Coco, Neil Osheroff, Ellen Solomon, David Grimwade

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Balanced chromosomal translocations that generate chimeric oncoproteins are considered to be initiating lesions in the pathogenesis of acute myeloid leukemia. The most frequent is the t(15;17)(q22;q21), which fuses the PML and RARA genes, giving rise to acute promyelocytic leukemia (APL). An increasing proportion of APL cases are therapy-related (t-APL), which develop following exposure to radiotherapy and/or chemotherapeutic agents that target DNA topoisomerase II (topoII), particularly mitoxantrone and epirubicin. To gain insights into molecular mechanisms underlying the formation of the t(15;17) we mapped the translocation breakpoints in a series of t-APLs, which revealed significant clustering according to the nature of the drug exposure. Remarkably, in approximately half of t-APL cases arising following mitoxantrone treatment for breast cancer or multiple sclerosis, the chromosome 15 breakpoint fell within an 8-bp "hotspot" region in PML intron 6, which was confirmed to be a preferential site of topoII-mediated DNA cleavage induced by mitoxantrone. Chromosome 15 breakpoints falling outside the "hotspot", and the corresponding RARA breakpoints were also shown to be functional topoII cleavage sites. The observation that particular regions of the PML and RARA loci are susceptible to topoII-mediated DNA damage induced by epirubicin and mitoxantrone may underlie the propensity of these agents to cause APL.

Original languageEnglish
Article numbere2011045
JournalMediterranean Journal of Hematology and Infectious Diseases
Volume3
Issue number1
DOIs
Publication statusPublished - 2011

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Mitoxantrone
Type II DNA Topoisomerase
Acute Promyelocytic Leukemia
Chromosome Breakpoints
Chromosomes, Human, Pair 15
Epirubicin
Genetic Translocation
DNA Cleavage
Oncogene Proteins
Acute Myeloid Leukemia
Introns
DNA Damage
Multiple Sclerosis
Cluster Analysis
Radiotherapy
Therapeutics
Breast Neoplasms
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Hematology
  • Infectious Diseases

Cite this

Joannides, M., Mays, A. N., Mistry, A. R., Hasan, S. K., Reiter, A., Wiemels, J. L., ... Grimwade, D. (2011). Molecular pathogenesis of secondary acute promyelocytic leukemia. Mediterranean Journal of Hematology and Infectious Diseases, 3(1), [e2011045]. https://doi.org/10.4084/MJHID.2011.045

Molecular pathogenesis of secondary acute promyelocytic leukemia. / Joannides, Melanie; Mays, Ashley N.; Mistry, Anita R.; Hasan, Syed Khizer; Reiter, Andreas; Wiemels, Joseph L.; Felix, Carolyn A.; Lo Coco, Francesco; Osheroff, Neil; Solomon, Ellen; Grimwade, David.

In: Mediterranean Journal of Hematology and Infectious Diseases, Vol. 3, No. 1, e2011045, 2011.

Research output: Contribution to journalArticle

Joannides, M, Mays, AN, Mistry, AR, Hasan, SK, Reiter, A, Wiemels, JL, Felix, CA, Lo Coco, F, Osheroff, N, Solomon, E & Grimwade, D 2011, 'Molecular pathogenesis of secondary acute promyelocytic leukemia', Mediterranean Journal of Hematology and Infectious Diseases, vol. 3, no. 1, e2011045. https://doi.org/10.4084/MJHID.2011.045
Joannides, Melanie ; Mays, Ashley N. ; Mistry, Anita R. ; Hasan, Syed Khizer ; Reiter, Andreas ; Wiemels, Joseph L. ; Felix, Carolyn A. ; Lo Coco, Francesco ; Osheroff, Neil ; Solomon, Ellen ; Grimwade, David. / Molecular pathogenesis of secondary acute promyelocytic leukemia. In: Mediterranean Journal of Hematology and Infectious Diseases. 2011 ; Vol. 3, No. 1.
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