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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
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.
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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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