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The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution

Recurrent submicroscopic deletions in genes affecting key cellular pathways are a hallmark of pediatric acute lymphoblastic leukemia (ALL). To gain more insight into the mechanism underlying these deletions, we have studied the occurrence and nature of abnormalities in one of these genes, the B-cell...

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Autores principales: Waanders, Esmé, Scheijen, Blanca, van der Meer, Laurens T., van Reijmersdal, Simon V., van Emst, Liesbeth, Kroeze, Yvet, Sonneveld, Edwin, Hoogerbrugge, Peter M., Geurts van Kessel, Ad, van Leeuwen, Frank N., Kuiper, Roland P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280973/
https://www.ncbi.nlm.nih.gov/pubmed/22359517
http://dx.doi.org/10.1371/journal.pgen.1002533
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author Waanders, Esmé
Scheijen, Blanca
van der Meer, Laurens T.
van Reijmersdal, Simon V.
van Emst, Liesbeth
Kroeze, Yvet
Sonneveld, Edwin
Hoogerbrugge, Peter M.
Geurts van Kessel, Ad
van Leeuwen, Frank N.
Kuiper, Roland P.
author_facet Waanders, Esmé
Scheijen, Blanca
van der Meer, Laurens T.
van Reijmersdal, Simon V.
van Emst, Liesbeth
Kroeze, Yvet
Sonneveld, Edwin
Hoogerbrugge, Peter M.
Geurts van Kessel, Ad
van Leeuwen, Frank N.
Kuiper, Roland P.
author_sort Waanders, Esmé
collection PubMed
description Recurrent submicroscopic deletions in genes affecting key cellular pathways are a hallmark of pediatric acute lymphoblastic leukemia (ALL). To gain more insight into the mechanism underlying these deletions, we have studied the occurrence and nature of abnormalities in one of these genes, the B-cell translocation gene 1 (BTG1), in a large cohort of pediatric ALL cases. BTG1 was found to be exclusively affected by genomic deletions, which were detected in 65 out of 722 B-cell precursor ALL (BCP-ALL) patient samples (9%), but not in 109 T-ALL cases. Eight different deletion sizes were identified, which all clustered at the telomeric site in a hotspot region within the second (and last) exon of the BTG1 gene, resulting in the expression of truncated BTG1 read-through transcripts. The presence of V(D)J recombination signal sequences at both sites of virtually all deletions strongly suggests illegitimate RAG1/RAG2-mediated recombination as the responsible mechanism. Moreover, high levels of histone H3 lysine 4 trimethylation (H3K4me3), which is known to tether the RAG enzyme complex to DNA, were found within the BTG1 gene body in BCP-ALL cells, but not T-ALL cells. BTG1 deletions were rarely found in hyperdiploid BCP-ALLs, but were predominant in other cytogenetic subgroups, including the ETV6-RUNX1 and BCR-ABL1 positive BCP-ALL subgroups. Through sensitive PCR-based screening, we identified multiple additional BTG1 deletions at the subclonal level in BCP-ALL, with equal cytogenetic distribution which, in some cases, grew out into the major clone at relapse. Taken together, our results indicate that BTG1 deletions may act as “drivers” of leukemogenesis in specific BCP-ALL subgroups, in which they can arise independently in multiple subclones at sites that are prone to aberrant RAG1/RAG2-mediated recombination events. These findings provide further evidence for a complex and multiclonal evolution of ALL.
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spelling pubmed-32809732012-02-22 The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution Waanders, Esmé Scheijen, Blanca van der Meer, Laurens T. van Reijmersdal, Simon V. van Emst, Liesbeth Kroeze, Yvet Sonneveld, Edwin Hoogerbrugge, Peter M. Geurts van Kessel, Ad van Leeuwen, Frank N. Kuiper, Roland P. PLoS Genet Research Article Recurrent submicroscopic deletions in genes affecting key cellular pathways are a hallmark of pediatric acute lymphoblastic leukemia (ALL). To gain more insight into the mechanism underlying these deletions, we have studied the occurrence and nature of abnormalities in one of these genes, the B-cell translocation gene 1 (BTG1), in a large cohort of pediatric ALL cases. BTG1 was found to be exclusively affected by genomic deletions, which were detected in 65 out of 722 B-cell precursor ALL (BCP-ALL) patient samples (9%), but not in 109 T-ALL cases. Eight different deletion sizes were identified, which all clustered at the telomeric site in a hotspot region within the second (and last) exon of the BTG1 gene, resulting in the expression of truncated BTG1 read-through transcripts. The presence of V(D)J recombination signal sequences at both sites of virtually all deletions strongly suggests illegitimate RAG1/RAG2-mediated recombination as the responsible mechanism. Moreover, high levels of histone H3 lysine 4 trimethylation (H3K4me3), which is known to tether the RAG enzyme complex to DNA, were found within the BTG1 gene body in BCP-ALL cells, but not T-ALL cells. BTG1 deletions were rarely found in hyperdiploid BCP-ALLs, but were predominant in other cytogenetic subgroups, including the ETV6-RUNX1 and BCR-ABL1 positive BCP-ALL subgroups. Through sensitive PCR-based screening, we identified multiple additional BTG1 deletions at the subclonal level in BCP-ALL, with equal cytogenetic distribution which, in some cases, grew out into the major clone at relapse. Taken together, our results indicate that BTG1 deletions may act as “drivers” of leukemogenesis in specific BCP-ALL subgroups, in which they can arise independently in multiple subclones at sites that are prone to aberrant RAG1/RAG2-mediated recombination events. These findings provide further evidence for a complex and multiclonal evolution of ALL. Public Library of Science 2012-02-16 /pmc/articles/PMC3280973/ /pubmed/22359517 http://dx.doi.org/10.1371/journal.pgen.1002533 Text en Waanders et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Waanders, Esmé
Scheijen, Blanca
van der Meer, Laurens T.
van Reijmersdal, Simon V.
van Emst, Liesbeth
Kroeze, Yvet
Sonneveld, Edwin
Hoogerbrugge, Peter M.
Geurts van Kessel, Ad
van Leeuwen, Frank N.
Kuiper, Roland P.
The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution
title The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution
title_full The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution
title_fullStr The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution
title_full_unstemmed The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution
title_short The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution
title_sort origin and nature of tightly clustered btg1 deletions in precursor b-cell acute lymphoblastic leukemia support a model of multiclonal evolution
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280973/
https://www.ncbi.nlm.nih.gov/pubmed/22359517
http://dx.doi.org/10.1371/journal.pgen.1002533
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