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Please use this identifier to cite or link to this item: http://hdl.handle.net/2108/1428

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contributor.advisorLo Coco, Francesco-
contributor.authorHasan, Syed Khizer-
date.accessioned2010-08-21T14:24:38Z-
date.available2010-08-21T14:24:38Z-
date.issued2010-08-21T14:24:38Z-
identifier.urihttp://hdl.handle.net/2108/1428-
description22. cicloen
description.abstractTherapy-related acute promyelocytic leukemia (t-APL) with the t(15;17) translocation is a well-recognized complication of cancer treatment with agents targeting topoisomerase II. However, cases are emerging following mitoxantrone therapy for multiple sclerosis (MS). Analysis of 12 cases of mitoxantrone-related t-APL in MS patients revealed an altered distribution of chromosome 15 breakpoints compared to de novo APL, biased towards disruption within PML intron 6 (11/12, 92% vs 622/1022, 61%: p=0.035). Despite this intron spanning ~1kb, the breakpoint in five mitoxantrone-treated patients fell within an 8bp region (1482-9) corresponding to the “hotspot” previously reported in t-APL complicating mitoxantrone-containing breast cancer therapy. Another shared breakpoint was identified within the ~17kb RARA intron 2 involving two t-APL cases arising after mitoxantrone treatment for MS and breast cancer, respectively. Analysis of PML and RARA genomic breakpoints in functional assays in 4 cases, including the shared RARA intron 2 breakpoint at 14446-49, confirmed each to be preferential sites of topoisomerase IIa-mediated DNA cleavage in the presence of mitoxantrone. This study further supports the presence of preferential sites of DNA damage induced by mitoxantrone in PML and RARA genes that may underlie the propensity to develop this particular subtype of leukemia following exposure to this agent. On extending our genomic analysis on therapy-related acute myeloid leukemia associated with t(16;21) (RUNX1-ETO2) arising after treatment of multiple sclerosis with mitoxantrone t-AML. We identified that genomic breakpoint region of RUNX1 contained a ATGCCCCAG nucleotide sequence showing ~90% homology to a “hotspot” DNA region ATGCCCTAG present in intron 6 of PML which was identified in therapy-related acute promyelocytic leukemia cases arising following treatment with mitoxantrone. Of note, in year 2000 Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology had approved mitoxantrone for progressive multiple sclerosis. Following the response to post-marketing findings such as potential risk of therapy related leukemia, decreased systolic function and heart failure, the US Food and Drug administration (FDA) has added a “black box” warning to the prescribing information for the mitoxantrone.en
description.abstractLa leucemia acuta promielocitica (APL) è caratterizzata dalla traslocazione t(15;17) con la formazione del gene chimerico PML-RARa. La APL secondaria a trattamento con inibitori della topoisomerasi II (t-APL) rappresenta una nota complicanza del trattamento chemioterapico in pazienti affetti da cancro. Tuttavia negli ultimi anni sono stati descritti parecchi casi di t-APL in pazienti affetti da sclerosi multipla (SM) e trattati con mitoxantrone. In 12 pazienti affetti da MS con t-APL secondaria all’uso di mitoxantrone, l’analisi genomica ha mostrato un’alterata distribuzione all’interno dell’introne 6 del gene PML dei punti di rottura sul cromosoma 15 rispetto alle APL de novo (11/12, 92% vs 622/1022, 61%: p=0.035). Infatti, nonostante l’introne 6 abbia una dimenzione di circa 1kb, in 5 pazienti con t-apl secondaria a MS il punto di rottura nel cromosoma 15 cade in una regione di 8 paia di basi (hotspot) precedentemente desritta in pazienti affetti da t-APL secondaria a carcinoma della mammella (KM). Inoltre, all’interno del gene RARa , che si estende per circa 17 kb abbiamo identificato un altro punto di rottura comune a due pazienti con t-APL secondaria a trattamento con mitoxantrone per MS e KM. In 4 casi, l’utilizzo di saggi funzionali ci ha permesso di confermare sia in PML che in RARa la presenza di loci che sono risultati essere siti preferenziali di taglio da parte della topoisomerasi IIa in presenza di mitoxantrone. Questo studio conferma ulteriormente la presenza nei geni PML e RARa di porzioni di DNA particolarmente sensibili al danno indotto da mitoxantrone che possono spiegare la propensione a sviluppare questo la t-APL in pazienti trattati con questo chemioterapico. Abbiamo esteso l’analisi genomica anche in un caso con leucemia acuta mieloide con traslocazione t(16;21) (RUNX1-ETO”) secondaria a sclerosi multipla trattata con mitoxantrone. Ancora una volta abbiamo identificato una regione di 9 paia di basi (ATGCCCCAG) che mostrava una omologia del 90% con la sequenza ATGCCCTAG presente nell’introne 6 di PML evidenziata nei pazienti con t-APL secondarie a trattamento con mitoxantrone. In questo contesto è da notare che l’Accademia Americana di Neurologia nel 2000 ha approvato il mitoxantrone per il trattamento della sclerosi multipla. Following the response to post-marketing findings such as potential risk of therapy related leukemia, decreased systolic function and heart failure, the US Food and Drug administration (FDA) has added a “black box” warning to the prescribing information for the mitoxantrone.en
description.tableofcontentsChapter 1:Introduction 1.1 Acute promyelocytic leukemia (APL) and therapy related APL (t-APL) 1.2 Therapy related acute myeloid leukemia 1.3 t-APL following multiple sclerosis and genetic variants of DNA double strand break repair genes 1.4 Aims and objectives 1.5 References to chapter 1. - Chapter 2: Mechanisms of the formation of t(15;17) in mitoxantrone related therapy related-APL following multiple sclerosis. - Chapter 3: Molecular analysis of the t(15;17) genomic breakpoints in epirubicin associated therapy-related APL following breast carcinoma. - Chapter 4: Analysis of t(15;17) chromosomal breakpoint sequences in therapy-related versus de novo APL. - Chapter 5: Genomic characterization of t(16;21) translocation in therapy-related acute myeloid leukemia. - Chapter 6: To study the genetic markers of susceptibility to t-APL and their association with multiple sclerosis. - Chapter 7: Conclusions and future directionsen
format.extent3957958 bytes-
format.mimetypeapplication/pdf-
language.isoenen
subjectacute promyelocytic leukemiaen
subjecttherapy related leukemiaen
subjectnon-homologous end joiningen
subjectmultiple sclerosisen
subject.classificationMED/15 Malattie del sangueen
titleInvestigation on the mechanisms underlying the chromosomal translocations in therapy-related acute myeloid leukemiasen
typeDoctoral thesisen
degree.nameEmatologiaen
degree.levelDottoratoen
degree.disciplineFacoltà di medicina e chirurgiaen
degree.grantorUniversità degli studi di Roma Tor Vergataen
date.dateofdefenseA.A. 2009/2010en
Appears in Collections:Tesi di dottorato in medicina

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