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Transcriptome Profiling of Pediatric Core Binding Factor AML

The t(8;21) and Inv(16) translocations disrupt the normal function of core binding factors alpha (CBFA) and beta (CBFB), respectively. These translocations represent two of the most common genomic abnormalities in acute myeloid leukemia (AML) patients, occurring in approximately 25% pediatric and 15...

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Autores principales: Hsu, Chih-Hao, Nguyen, Cu, Yan, Chunhua, Ries, Rhonda E., Chen, Qing-Rong, Hu, Ying, Ostronoff, Fabiana, Stirewalt, Derek L., Komatsoulis, George, Levy, Shawn, Meerzaman, Daoud, Meshinchi, Soheil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580636/
https://www.ncbi.nlm.nih.gov/pubmed/26397705
http://dx.doi.org/10.1371/journal.pone.0138782
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author Hsu, Chih-Hao
Nguyen, Cu
Yan, Chunhua
Ries, Rhonda E.
Chen, Qing-Rong
Hu, Ying
Ostronoff, Fabiana
Stirewalt, Derek L.
Komatsoulis, George
Levy, Shawn
Meerzaman, Daoud
Meshinchi, Soheil
author_facet Hsu, Chih-Hao
Nguyen, Cu
Yan, Chunhua
Ries, Rhonda E.
Chen, Qing-Rong
Hu, Ying
Ostronoff, Fabiana
Stirewalt, Derek L.
Komatsoulis, George
Levy, Shawn
Meerzaman, Daoud
Meshinchi, Soheil
author_sort Hsu, Chih-Hao
collection PubMed
description The t(8;21) and Inv(16) translocations disrupt the normal function of core binding factors alpha (CBFA) and beta (CBFB), respectively. These translocations represent two of the most common genomic abnormalities in acute myeloid leukemia (AML) patients, occurring in approximately 25% pediatric and 15% of adult with this malignancy. Both translocations are associated with favorable clinical outcomes after intensive chemotherapy, and given the perceived mechanistic similarities, patients with these translocations are frequently referred to as having CBF-AML. It remains uncertain as to whether, collectively, these translocations are mechanistically the same or impact different pathways in subtle ways that have both biological and clinical significance. Therefore, we used transcriptome sequencing (RNA-seq) to investigate the similarities and differences in genes and pathways between these subtypes of pediatric AMLs. Diagnostic RNA from patients with t(8;21) (N = 17), Inv(16) (N = 14), and normal karyotype (NK, N = 33) were subjected to RNA-seq. Analyses compared the transcriptomes across these three cytogenetic subtypes, using the NK cohort as the control. A total of 1291 genes in t(8;21) and 474 genes in Inv(16) were differentially expressed relative to the NK controls, with 198 genes differentially expressed in both subtypes. The majority of these genes (175/198; binomial test p-value < 10(−30)) are consistent in expression changes among the two subtypes suggesting the expression profiles are more similar between the CBF cohorts than in the NK cohort. Our analysis also revealed alternative splicing events (ASEs) differentially expressed across subtypes, with 337 t(8;21)-specific and 407 Inv(16)-specific ASEs detected, the majority of which were acetylated proteins (p = 1.5x10(-51) and p = 1.8x10(-54) for the two subsets). In addition to known fusions, we identified and verified 16 de novo fusions in 43 patients, including three fusions involving NUP98 in six patients. Clustering of differentially expressed genes indicated that the homeobox (HOX) gene family, including two transcription factors (MEIS1 and NKX2-3) were down-regulated in CBF compared to NK samples. This finding supports existing data that the dysregulation of HOX genes play a central role in biology CBF-AML hematopoiesis. These data provide comprehensive transcriptome profiling of CBF-AML and delineate genes and pathways that are differentially expressed, providing insights into the shared biology as well as differences in the two CBF subsets.
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spelling pubmed-45806362015-10-01 Transcriptome Profiling of Pediatric Core Binding Factor AML Hsu, Chih-Hao Nguyen, Cu Yan, Chunhua Ries, Rhonda E. Chen, Qing-Rong Hu, Ying Ostronoff, Fabiana Stirewalt, Derek L. Komatsoulis, George Levy, Shawn Meerzaman, Daoud Meshinchi, Soheil PLoS One Research Article The t(8;21) and Inv(16) translocations disrupt the normal function of core binding factors alpha (CBFA) and beta (CBFB), respectively. These translocations represent two of the most common genomic abnormalities in acute myeloid leukemia (AML) patients, occurring in approximately 25% pediatric and 15% of adult with this malignancy. Both translocations are associated with favorable clinical outcomes after intensive chemotherapy, and given the perceived mechanistic similarities, patients with these translocations are frequently referred to as having CBF-AML. It remains uncertain as to whether, collectively, these translocations are mechanistically the same or impact different pathways in subtle ways that have both biological and clinical significance. Therefore, we used transcriptome sequencing (RNA-seq) to investigate the similarities and differences in genes and pathways between these subtypes of pediatric AMLs. Diagnostic RNA from patients with t(8;21) (N = 17), Inv(16) (N = 14), and normal karyotype (NK, N = 33) were subjected to RNA-seq. Analyses compared the transcriptomes across these three cytogenetic subtypes, using the NK cohort as the control. A total of 1291 genes in t(8;21) and 474 genes in Inv(16) were differentially expressed relative to the NK controls, with 198 genes differentially expressed in both subtypes. The majority of these genes (175/198; binomial test p-value < 10(−30)) are consistent in expression changes among the two subtypes suggesting the expression profiles are more similar between the CBF cohorts than in the NK cohort. Our analysis also revealed alternative splicing events (ASEs) differentially expressed across subtypes, with 337 t(8;21)-specific and 407 Inv(16)-specific ASEs detected, the majority of which were acetylated proteins (p = 1.5x10(-51) and p = 1.8x10(-54) for the two subsets). In addition to known fusions, we identified and verified 16 de novo fusions in 43 patients, including three fusions involving NUP98 in six patients. Clustering of differentially expressed genes indicated that the homeobox (HOX) gene family, including two transcription factors (MEIS1 and NKX2-3) were down-regulated in CBF compared to NK samples. This finding supports existing data that the dysregulation of HOX genes play a central role in biology CBF-AML hematopoiesis. These data provide comprehensive transcriptome profiling of CBF-AML and delineate genes and pathways that are differentially expressed, providing insights into the shared biology as well as differences in the two CBF subsets. Public Library of Science 2015-09-23 /pmc/articles/PMC4580636/ /pubmed/26397705 http://dx.doi.org/10.1371/journal.pone.0138782 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Hsu, Chih-Hao
Nguyen, Cu
Yan, Chunhua
Ries, Rhonda E.
Chen, Qing-Rong
Hu, Ying
Ostronoff, Fabiana
Stirewalt, Derek L.
Komatsoulis, George
Levy, Shawn
Meerzaman, Daoud
Meshinchi, Soheil
Transcriptome Profiling of Pediatric Core Binding Factor AML
title Transcriptome Profiling of Pediatric Core Binding Factor AML
title_full Transcriptome Profiling of Pediatric Core Binding Factor AML
title_fullStr Transcriptome Profiling of Pediatric Core Binding Factor AML
title_full_unstemmed Transcriptome Profiling of Pediatric Core Binding Factor AML
title_short Transcriptome Profiling of Pediatric Core Binding Factor AML
title_sort transcriptome profiling of pediatric core binding factor aml
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580636/
https://www.ncbi.nlm.nih.gov/pubmed/26397705
http://dx.doi.org/10.1371/journal.pone.0138782
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