Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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
_version_ 1784680774917685248
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
work_keys_str_mv AT stasiksebastian pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT kramermichael pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT zukunftsven pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT rolligchristoph pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT baldusclaudiad pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT platzbeckeruwe pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT servehubert pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT mullertidowcarsten pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT schafereckartkerstin pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT kaufmannmartin pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT krausestefan pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT sauertim pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT hanelmathias pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT neubauerandreas pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT ehningergerhard pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT bornhausermartin pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT scheteligjohannes pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT middekejanm pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd
AT thiedechristian pointmutationsintheflt3itdregionarerarebutrecurrentalterationsinadultamlandassociatedwithconcomitantkmt2aptd