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Different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood
Deletion of chromosome 9p21 is a crucial event for the development of several cancers including acute lymphoblastic leukemia (ALL). Double strand breaks (DSBs) triggering 9p21 deletions in ALL have been reported to occur at a few defined sites by illegitimate action of the V(D)J recombination activa...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Springer-Verlag
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762534/ https://www.ncbi.nlm.nih.gov/pubmed/19484265 http://dx.doi.org/10.1007/s00439-009-0689-7 |
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author | Novara, Francesca Beri, Silvana Bernardo, Maria Ester Bellazzi, Riccardo Malovini, Alberto Ciccone, Roberto Cometa, Angela Maria Locatelli, Franco Giorda, Roberto Zuffardi, Orsetta |
author_facet | Novara, Francesca Beri, Silvana Bernardo, Maria Ester Bellazzi, Riccardo Malovini, Alberto Ciccone, Roberto Cometa, Angela Maria Locatelli, Franco Giorda, Roberto Zuffardi, Orsetta |
author_sort | Novara, Francesca |
collection | PubMed |
description | Deletion of chromosome 9p21 is a crucial event for the development of several cancers including acute lymphoblastic leukemia (ALL). Double strand breaks (DSBs) triggering 9p21 deletions in ALL have been reported to occur at a few defined sites by illegitimate action of the V(D)J recombination activating protein complex. We have cloned 23 breakpoint junctions for a total of 46 breakpoints in 17 childhood ALL (9 B- and 8 T-lineages) showing different size deletions at one or both homologous chromosomes 9 to investigate which particular sequences make the region susceptible to interstitial deletion. We found that half of 9p21 deletion breakpoints were mediated by ectopic V(D)J recombination mechanisms whereas the remaining half were associated to repeated sequences, including some with potential for non-B DNA structure formation. Other mechanisms, such as microhomology-mediated repair, that are common in other cancers, play only a very minor role in ALL. Nucleotide insertions at breakpoint junctions and microinversions flanking the breakpoints have been detected at 20/23 and 2/23 breakpoint junctions, respectively, both in the presence of recombination signal sequence (RSS)-like sequences and of other unspecific sequences. The majority of breakpoints were unique except for two cases, both T-ALL, showing identical deletions. Four of the 46 breakpoints coincide with those reported in other cases, thus confirming the presence of recurrent deletion hotspots. Among the six cases with heterozygous 9p deletions, we found that the remaining CDKN2A and CDKN2B alleles were hypermethylated at CpG islands. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00439-009-0689-7) contains supplementary material, which is available to authorized users. |
format | Text |
id | pubmed-2762534 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Springer-Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-27625342009-10-21 Different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood Novara, Francesca Beri, Silvana Bernardo, Maria Ester Bellazzi, Riccardo Malovini, Alberto Ciccone, Roberto Cometa, Angela Maria Locatelli, Franco Giorda, Roberto Zuffardi, Orsetta Hum Genet Original Investigation Deletion of chromosome 9p21 is a crucial event for the development of several cancers including acute lymphoblastic leukemia (ALL). Double strand breaks (DSBs) triggering 9p21 deletions in ALL have been reported to occur at a few defined sites by illegitimate action of the V(D)J recombination activating protein complex. We have cloned 23 breakpoint junctions for a total of 46 breakpoints in 17 childhood ALL (9 B- and 8 T-lineages) showing different size deletions at one or both homologous chromosomes 9 to investigate which particular sequences make the region susceptible to interstitial deletion. We found that half of 9p21 deletion breakpoints were mediated by ectopic V(D)J recombination mechanisms whereas the remaining half were associated to repeated sequences, including some with potential for non-B DNA structure formation. Other mechanisms, such as microhomology-mediated repair, that are common in other cancers, play only a very minor role in ALL. Nucleotide insertions at breakpoint junctions and microinversions flanking the breakpoints have been detected at 20/23 and 2/23 breakpoint junctions, respectively, both in the presence of recombination signal sequence (RSS)-like sequences and of other unspecific sequences. The majority of breakpoints were unique except for two cases, both T-ALL, showing identical deletions. Four of the 46 breakpoints coincide with those reported in other cases, thus confirming the presence of recurrent deletion hotspots. Among the six cases with heterozygous 9p deletions, we found that the remaining CDKN2A and CDKN2B alleles were hypermethylated at CpG islands. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00439-009-0689-7) contains supplementary material, which is available to authorized users. Springer-Verlag 2009-05-30 2009 /pmc/articles/PMC2762534/ /pubmed/19484265 http://dx.doi.org/10.1007/s00439-009-0689-7 Text en © The Author(s) 2009 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Original Investigation Novara, Francesca Beri, Silvana Bernardo, Maria Ester Bellazzi, Riccardo Malovini, Alberto Ciccone, Roberto Cometa, Angela Maria Locatelli, Franco Giorda, Roberto Zuffardi, Orsetta Different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood |
title | Different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood |
title_full | Different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood |
title_fullStr | Different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood |
title_full_unstemmed | Different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood |
title_short | Different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood |
title_sort | different molecular mechanisms causing 9p21 deletions in acute lymphoblastic leukemia of childhood |
topic | Original Investigation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762534/ https://www.ncbi.nlm.nih.gov/pubmed/19484265 http://dx.doi.org/10.1007/s00439-009-0689-7 |
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