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Point Mutations in the FLT3-ITD Region Are Rare but Recurrent Alterations in Adult AML and Associated With Concomitant KMT2A-PTD
FLT3-ITD mutations are common druggable alterations in patients with acute myeloid leukemia (AML) and associated with poor prognosis. Beside typical ITD mutations, point mutations and deletions in the juxtamembrane domain (JMD) have been observed. However, due to the low frequency of these alteratio...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8977490/ https://www.ncbi.nlm.nih.gov/pubmed/35387132 http://dx.doi.org/10.3389/fonc.2022.862991 |
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author | Stasik, Sebastian Kramer, Michael Zukunft, Sven Röllig, Christoph Baldus, Claudia D. Platzbecker, Uwe Serve, Hubert Müller-Tidow, Carsten Schäfer-Eckart, Kerstin Kaufmann, Martin Krause, Stefan Sauer, Tim Hänel, Mathias Neubauer, Andreas Ehninger, Gerhard Bornhäuser, Martin Schetelig, Johannes Middeke, Jan M. Thiede, Christian |
author_facet | Stasik, Sebastian Kramer, Michael Zukunft, Sven Röllig, Christoph Baldus, Claudia D. Platzbecker, Uwe Serve, Hubert Müller-Tidow, Carsten Schäfer-Eckart, Kerstin Kaufmann, Martin Krause, Stefan Sauer, Tim Hänel, Mathias Neubauer, Andreas Ehninger, Gerhard Bornhäuser, Martin Schetelig, Johannes Middeke, Jan M. Thiede, Christian |
author_sort | Stasik, Sebastian |
collection | PubMed |
description | FLT3-ITD mutations are common druggable alterations in patients with acute myeloid leukemia (AML) and associated with poor prognosis. Beside typical ITD mutations, point mutations and deletions in the juxtamembrane domain (JMD) have been observed. However, due to the low frequency of these alterations, there is only limited information on molecular and clinical associations. To evaluate the prognostic impact of non-ITD mutations in the FLT3 JMD region, we analyzed a large cohort of 1,539 adult AML patients treated in different protocols of the Study Alliance Leukemia, using next-generation sequencing. Non-ITD point mutations and deletions within the FLT3 JMD were identified with a prevalence of ~1.23% (n = 19). Both FLT3-ITD and non-ITD mutations were associated with a higher rate of NPM1 (42%–61%; p < 0.001) and DNMT3A mutations (37%–43%; p < 0.001), as well as an increased percentage of peripheral blood (54%–65%) and bone marrow blast cells (74%; p < 0.001), compared to FLT3-wild-type patients. Most significantly, AML patients with FLT3 non-ITD mutations had a higher rate of concomitant KMT2A-PTD mutations (37.5%; p < 0.001) as compared to FLT3-ITD (7%) or FLT3-wild-type cases (4.5%). In a multivariable analysis, FLT3 non-ITD mutations were not an independent prognostic factor. However, patients with dual FLT3 non-ITD and KMT2A-PTD mutations showed a trend for inferior outcome, which points at a functional interaction in this subset of AML. |
format | Online Article Text |
id | pubmed-8977490 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89774902022-04-05 Point Mutations in the FLT3-ITD Region Are Rare but Recurrent Alterations in Adult AML and Associated With Concomitant KMT2A-PTD Stasik, Sebastian Kramer, Michael Zukunft, Sven Röllig, Christoph Baldus, Claudia D. Platzbecker, Uwe Serve, Hubert Müller-Tidow, Carsten Schäfer-Eckart, Kerstin Kaufmann, Martin Krause, Stefan Sauer, Tim Hänel, Mathias Neubauer, Andreas Ehninger, Gerhard Bornhäuser, Martin Schetelig, Johannes Middeke, Jan M. Thiede, Christian Front Oncol Oncology FLT3-ITD mutations are common druggable alterations in patients with acute myeloid leukemia (AML) and associated with poor prognosis. Beside typical ITD mutations, point mutations and deletions in the juxtamembrane domain (JMD) have been observed. However, due to the low frequency of these alterations, there is only limited information on molecular and clinical associations. To evaluate the prognostic impact of non-ITD mutations in the FLT3 JMD region, we analyzed a large cohort of 1,539 adult AML patients treated in different protocols of the Study Alliance Leukemia, using next-generation sequencing. Non-ITD point mutations and deletions within the FLT3 JMD were identified with a prevalence of ~1.23% (n = 19). Both FLT3-ITD and non-ITD mutations were associated with a higher rate of NPM1 (42%–61%; p < 0.001) and DNMT3A mutations (37%–43%; p < 0.001), as well as an increased percentage of peripheral blood (54%–65%) and bone marrow blast cells (74%; p < 0.001), compared to FLT3-wild-type patients. Most significantly, AML patients with FLT3 non-ITD mutations had a higher rate of concomitant KMT2A-PTD mutations (37.5%; p < 0.001) as compared to FLT3-ITD (7%) or FLT3-wild-type cases (4.5%). In a multivariable analysis, FLT3 non-ITD mutations were not an independent prognostic factor. However, patients with dual FLT3 non-ITD and KMT2A-PTD mutations showed a trend for inferior outcome, which points at a functional interaction in this subset of AML. Frontiers Media S.A. 2022-03-21 /pmc/articles/PMC8977490/ /pubmed/35387132 http://dx.doi.org/10.3389/fonc.2022.862991 Text en Copyright © 2022 Stasik, Kramer, Zukunft, Röllig, Baldus, Platzbecker, Serve, Müller-Tidow, Schäfer-Eckart, Kaufmann, Krause, Sauer, Hänel, Neubauer, Ehninger, Bornhäuser, Schetelig, Middeke and Thiede https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Stasik, Sebastian Kramer, Michael Zukunft, Sven Röllig, Christoph Baldus, Claudia D. Platzbecker, Uwe Serve, Hubert Müller-Tidow, Carsten Schäfer-Eckart, Kerstin Kaufmann, Martin Krause, Stefan Sauer, Tim Hänel, Mathias Neubauer, Andreas Ehninger, Gerhard Bornhäuser, Martin Schetelig, Johannes Middeke, Jan M. Thiede, Christian Point Mutations in the FLT3-ITD Region Are Rare but Recurrent Alterations in Adult AML and Associated With Concomitant KMT2A-PTD |
title | Point Mutations in the FLT3-ITD Region Are Rare but Recurrent Alterations in Adult AML and Associated With Concomitant KMT2A-PTD |
title_full | Point Mutations in the FLT3-ITD Region Are Rare but Recurrent Alterations in Adult AML and Associated With Concomitant KMT2A-PTD |
title_fullStr | Point Mutations in the FLT3-ITD Region Are Rare but Recurrent Alterations in Adult AML and Associated With Concomitant KMT2A-PTD |
title_full_unstemmed | Point Mutations in the FLT3-ITD Region Are Rare but Recurrent Alterations in Adult AML and Associated With Concomitant KMT2A-PTD |
title_short | Point Mutations in the FLT3-ITD Region Are Rare but Recurrent Alterations in Adult AML and Associated With Concomitant KMT2A-PTD |
title_sort | point mutations in the flt3-itd region are rare but recurrent alterations in adult aml and associated with concomitant kmt2a-ptd |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8977490/ https://www.ncbi.nlm.nih.gov/pubmed/35387132 http://dx.doi.org/10.3389/fonc.2022.862991 |
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