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Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT 3‐ITD AML
Fms‐like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations, common in pediatric acute myeloid leukemia (AML), associate with early relapse and poor prognosis. Past studies have suggested additional cooperative mutations are required for leukemogenesis in FLT3‐ITD+ AML. Using RNA s...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853146/ https://www.ncbi.nlm.nih.gov/pubmed/31350825 http://dx.doi.org/10.1111/cts.12669 |
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author | Buelow, Daelynn R. Pounds, Stanley B. Wang, Yong‐Dong Shi, Lei Li, Yongjin Finkelstein, David Shurtleff, Sheila Neale, Geoffrey Inaba, Hiroto Ribeiro, Raul C. Palumbo, Reid Garrison, Dominique Orwick, Shelley J. Blachly, James S. Kroll, Karl Byrd, John C. Gruber, Tanja A. Rubnitz, Jeffrey E. Baker, Sharyn D. |
author_facet | Buelow, Daelynn R. Pounds, Stanley B. Wang, Yong‐Dong Shi, Lei Li, Yongjin Finkelstein, David Shurtleff, Sheila Neale, Geoffrey Inaba, Hiroto Ribeiro, Raul C. Palumbo, Reid Garrison, Dominique Orwick, Shelley J. Blachly, James S. Kroll, Karl Byrd, John C. Gruber, Tanja A. Rubnitz, Jeffrey E. Baker, Sharyn D. |
author_sort | Buelow, Daelynn R. |
collection | PubMed |
description | Fms‐like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations, common in pediatric acute myeloid leukemia (AML), associate with early relapse and poor prognosis. Past studies have suggested additional cooperative mutations are required for leukemogenesis in FLT3‐ITD+ AML. Using RNA sequencing and a next‐generation targeted gene panel, we broadly characterize the co‐occurring genomic alterations in pediatric cytogenetically normal (CN) FLT3‐ITD+ AML to gain a deeper understanding of the clonal patterns and heterogeneity at diagnosis and relapse. We show that chimeric transcripts were present in 21 of 34 (62%) of de novo samples, 2 (6%) of these samples included a rare reoccurring fusion partner BCL11B. At diagnosis, the median number of mutations other than FLT3 per patient was 1 (range 0–3), which involved 8 gene pathways; WT1 and NPM1 mutations were frequently observed (35% and 24%, respectively). Fusion transcripts and high variant allele frequency (VAF) mutants, which included WT1,NPM1,SMARCA2,RAD21, and TYK2, were retained from diagnosis to relapse. We did observe reduction in VAF of simple or single mutation clones, but VAFs were preserved or expanded in more complex clones with multiple mutations. Our data provide the first insight into the genomic complexity of pediatric CN FLT3‐ITD+ AML and could help stratify future targeted treatment strategies. |
format | Online Article Text |
id | pubmed-6853146 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-68531462019-12-16 Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT 3‐ITD AML Buelow, Daelynn R. Pounds, Stanley B. Wang, Yong‐Dong Shi, Lei Li, Yongjin Finkelstein, David Shurtleff, Sheila Neale, Geoffrey Inaba, Hiroto Ribeiro, Raul C. Palumbo, Reid Garrison, Dominique Orwick, Shelley J. Blachly, James S. Kroll, Karl Byrd, John C. Gruber, Tanja A. Rubnitz, Jeffrey E. Baker, Sharyn D. Clin Transl Sci Research Fms‐like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations, common in pediatric acute myeloid leukemia (AML), associate with early relapse and poor prognosis. Past studies have suggested additional cooperative mutations are required for leukemogenesis in FLT3‐ITD+ AML. Using RNA sequencing and a next‐generation targeted gene panel, we broadly characterize the co‐occurring genomic alterations in pediatric cytogenetically normal (CN) FLT3‐ITD+ AML to gain a deeper understanding of the clonal patterns and heterogeneity at diagnosis and relapse. We show that chimeric transcripts were present in 21 of 34 (62%) of de novo samples, 2 (6%) of these samples included a rare reoccurring fusion partner BCL11B. At diagnosis, the median number of mutations other than FLT3 per patient was 1 (range 0–3), which involved 8 gene pathways; WT1 and NPM1 mutations were frequently observed (35% and 24%, respectively). Fusion transcripts and high variant allele frequency (VAF) mutants, which included WT1,NPM1,SMARCA2,RAD21, and TYK2, were retained from diagnosis to relapse. We did observe reduction in VAF of simple or single mutation clones, but VAFs were preserved or expanded in more complex clones with multiple mutations. Our data provide the first insight into the genomic complexity of pediatric CN FLT3‐ITD+ AML and could help stratify future targeted treatment strategies. John Wiley and Sons Inc. 2019-08-20 2019-11 /pmc/articles/PMC6853146/ /pubmed/31350825 http://dx.doi.org/10.1111/cts.12669 Text en © 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Buelow, Daelynn R. Pounds, Stanley B. Wang, Yong‐Dong Shi, Lei Li, Yongjin Finkelstein, David Shurtleff, Sheila Neale, Geoffrey Inaba, Hiroto Ribeiro, Raul C. Palumbo, Reid Garrison, Dominique Orwick, Shelley J. Blachly, James S. Kroll, Karl Byrd, John C. Gruber, Tanja A. Rubnitz, Jeffrey E. Baker, Sharyn D. Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT 3‐ITD AML |
title | Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT
3‐ITD AML |
title_full | Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT
3‐ITD AML |
title_fullStr | Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT
3‐ITD AML |
title_full_unstemmed | Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT
3‐ITD AML |
title_short | Uncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT
3‐ITD AML |
title_sort | uncovering the genomic landscape in newly diagnosed and relapsed pediatric cytogenetically normal flt
3‐itd aml |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853146/ https://www.ncbi.nlm.nih.gov/pubmed/31350825 http://dx.doi.org/10.1111/cts.12669 |
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