MOLECULAR PATHOGENESIS OF SECONDARY ACUTE PROMYELOCYTIC LEUKEMIA
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 increas...
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| Format: | Article |
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PAGEPress Publications
2011-10-01
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| Series: | Mediterranean Journal of Hematology and Infectious Diseases |
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| Online Access: | http://www.mjhid.org/index.php/mjhid/article/view/301 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Melanie Joannides |
| collection | DOAJ |
| description | 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 the nature of the drug exposure. Remarkably, in approximately half of t-APL cases arising following mitoxantrone treatment for breast carcinoma 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. |
| format | Article |
| id | doaj-art-ec9e8c9f53b6491fb0f40175f05e8434 |
| institution | Kabale University |
| issn | 2035-3006 |
| language | English |
| publishDate | 2011-10-01 |
| publisher | PAGEPress Publications |
| record_format | Article |
| series | Mediterranean Journal of Hematology and Infectious Diseases |
| spelling | doaj-art-ec9e8c9f53b6491fb0f40175f05e84342025-01-02T06:26:04ZengPAGEPress PublicationsMediterranean Journal of Hematology and Infectious Diseases2035-30062011-10-0131e2011045e201104510.4084/mjhid.2011.045193MOLECULAR PATHOGENESIS OF SECONDARY ACUTE PROMYELOCYTIC LEUKEMIAMelanie Joannides0Ashley N MaysAnita R Mistry1Syed Khizer HasanAndreas ReiterJoseph L WiemelsCarolyn A FelixFrancesco Lo-CocoNeil OsheroffEllen SolomonDavid Grimwade2Department of Medical & Molecular Genetics, King’s College London School of Medicine, UK.,Department of Medical & Molecular Genetics, King’s College London School of Medicine, UK.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 the nature of the drug exposure. Remarkably, in approximately half of t-APL cases arising following mitoxantrone treatment for breast carcinoma 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.http://www.mjhid.org/index.php/mjhid/article/view/301Leukemia, therapy related leukemia, Acute promyelocytic leukemia |
| spellingShingle | 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 MOLECULAR PATHOGENESIS OF SECONDARY ACUTE PROMYELOCYTIC LEUKEMIA Mediterranean Journal of Hematology and Infectious Diseases Leukemia, therapy related leukemia, Acute promyelocytic leukemia |
| title | MOLECULAR PATHOGENESIS OF SECONDARY ACUTE PROMYELOCYTIC LEUKEMIA |
| title_full | MOLECULAR PATHOGENESIS OF SECONDARY ACUTE PROMYELOCYTIC LEUKEMIA |
| title_fullStr | MOLECULAR PATHOGENESIS OF SECONDARY ACUTE PROMYELOCYTIC LEUKEMIA |
| title_full_unstemmed | MOLECULAR PATHOGENESIS OF SECONDARY ACUTE PROMYELOCYTIC LEUKEMIA |
| title_short | MOLECULAR PATHOGENESIS OF SECONDARY ACUTE PROMYELOCYTIC LEUKEMIA |
| title_sort | molecular pathogenesis of secondary acute promyelocytic leukemia |
| topic | Leukemia, therapy related leukemia, Acute promyelocytic leukemia |
| url | http://www.mjhid.org/index.php/mjhid/article/view/301 |
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