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Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome

Functional perturbations of the cohesin complex with subsequent changes in chromatin structure and replication are reported in a multitude of cancers including acute myeloid leukemia (AML). Mutations of its STAG2 subunit may predict unfavorable risk as recognized by the 2022 European Leukemia Net re...

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Autores principales: Eckardt, Jan-Niklas, Stasik, Sebastian, Röllig, Christoph, Sauer, Tim, Scholl, Sebastian, Hochhaus, Andreas, Crysandt, Martina, Brümmendorf, Tim H., Naumann, Ralph, Steffen, Björn, Kunzmann, Volker, Einsele, Hermann, Schaich, Markus, Burchert, Andreas, Neubauer, Andreas, Schäfer-Eckart, Kerstin, Schliemann, Christoph, Krause, Stefan W., Herbst, Regina, Hänel, Mathias, Hanoun, Maher, Kaiser, Ulrich, Kaufmann, Martin, Rácil, Zdenek, Mayer, Jiri, Cerqueira, Tiago, Kroschinsky, Frank, Berdel, Wolfgang E., Serve, Hubert, Müller-Tidow, Carsten, Platzbecker, Uwe, Baldus, Claudia D., Schetelig, Johannes, Siepmann, Timo, Bornhäuser, Martin, Middeke, Jan Moritz, Thiede, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9873811/
https://www.ncbi.nlm.nih.gov/pubmed/36693840
http://dx.doi.org/10.1038/s41408-023-00790-1
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author Eckardt, Jan-Niklas
Stasik, Sebastian
Röllig, Christoph
Sauer, Tim
Scholl, Sebastian
Hochhaus, Andreas
Crysandt, Martina
Brümmendorf, Tim H.
Naumann, Ralph
Steffen, Björn
Kunzmann, Volker
Einsele, Hermann
Schaich, Markus
Burchert, Andreas
Neubauer, Andreas
Schäfer-Eckart, Kerstin
Schliemann, Christoph
Krause, Stefan W.
Herbst, Regina
Hänel, Mathias
Hanoun, Maher
Kaiser, Ulrich
Kaufmann, Martin
Rácil, Zdenek
Mayer, Jiri
Cerqueira, Tiago
Kroschinsky, Frank
Berdel, Wolfgang E.
Serve, Hubert
Müller-Tidow, Carsten
Platzbecker, Uwe
Baldus, Claudia D.
Schetelig, Johannes
Siepmann, Timo
Bornhäuser, Martin
Middeke, Jan Moritz
Thiede, Christian
author_facet Eckardt, Jan-Niklas
Stasik, Sebastian
Röllig, Christoph
Sauer, Tim
Scholl, Sebastian
Hochhaus, Andreas
Crysandt, Martina
Brümmendorf, Tim H.
Naumann, Ralph
Steffen, Björn
Kunzmann, Volker
Einsele, Hermann
Schaich, Markus
Burchert, Andreas
Neubauer, Andreas
Schäfer-Eckart, Kerstin
Schliemann, Christoph
Krause, Stefan W.
Herbst, Regina
Hänel, Mathias
Hanoun, Maher
Kaiser, Ulrich
Kaufmann, Martin
Rácil, Zdenek
Mayer, Jiri
Cerqueira, Tiago
Kroschinsky, Frank
Berdel, Wolfgang E.
Serve, Hubert
Müller-Tidow, Carsten
Platzbecker, Uwe
Baldus, Claudia D.
Schetelig, Johannes
Siepmann, Timo
Bornhäuser, Martin
Middeke, Jan Moritz
Thiede, Christian
author_sort Eckardt, Jan-Niklas
collection PubMed
description Functional perturbations of the cohesin complex with subsequent changes in chromatin structure and replication are reported in a multitude of cancers including acute myeloid leukemia (AML). Mutations of its STAG2 subunit may predict unfavorable risk as recognized by the 2022 European Leukemia Net recommendations, but the underlying evidence is limited by small sample sizes and conflicting observations regarding clinical outcomes, as well as scarce information on other cohesion complex subunits. We retrospectively analyzed data from a multi-center cohort of 1615 intensively treated AML patients and identified distinct co-mutational patters for mutations of STAG2, which were associated with normal karyotypes (NK) and concomitant mutations in IDH2, RUNX1, BCOR, ASXL1, and SRSF2. Mutated RAD21 was associated with NK, mutated EZH2, KRAS, CBL, and NPM1. Patients harboring mutated STAG2 were older and presented with decreased white blood cell, bone marrow and peripheral blood blast counts. Overall, neither mutated STAG2, RAD21, SMC1A nor SMC3 displayed any significant, independent effect on clinical outcomes defined as complete remission, event-free, relapse-free or overall survival. However, we found almost complete mutual exclusivity of genetic alterations of individual cohesin subunits. This mutual exclusivity may be the basis for therapeutic strategies via synthetic lethality in cohesin mutated AML.
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spelling pubmed-98738112023-01-26 Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome Eckardt, Jan-Niklas Stasik, Sebastian Röllig, Christoph Sauer, Tim Scholl, Sebastian Hochhaus, Andreas Crysandt, Martina Brümmendorf, Tim H. Naumann, Ralph Steffen, Björn Kunzmann, Volker Einsele, Hermann Schaich, Markus Burchert, Andreas Neubauer, Andreas Schäfer-Eckart, Kerstin Schliemann, Christoph Krause, Stefan W. Herbst, Regina Hänel, Mathias Hanoun, Maher Kaiser, Ulrich Kaufmann, Martin Rácil, Zdenek Mayer, Jiri Cerqueira, Tiago Kroschinsky, Frank Berdel, Wolfgang E. Serve, Hubert Müller-Tidow, Carsten Platzbecker, Uwe Baldus, Claudia D. Schetelig, Johannes Siepmann, Timo Bornhäuser, Martin Middeke, Jan Moritz Thiede, Christian Blood Cancer J Article Functional perturbations of the cohesin complex with subsequent changes in chromatin structure and replication are reported in a multitude of cancers including acute myeloid leukemia (AML). Mutations of its STAG2 subunit may predict unfavorable risk as recognized by the 2022 European Leukemia Net recommendations, but the underlying evidence is limited by small sample sizes and conflicting observations regarding clinical outcomes, as well as scarce information on other cohesion complex subunits. We retrospectively analyzed data from a multi-center cohort of 1615 intensively treated AML patients and identified distinct co-mutational patters for mutations of STAG2, which were associated with normal karyotypes (NK) and concomitant mutations in IDH2, RUNX1, BCOR, ASXL1, and SRSF2. Mutated RAD21 was associated with NK, mutated EZH2, KRAS, CBL, and NPM1. Patients harboring mutated STAG2 were older and presented with decreased white blood cell, bone marrow and peripheral blood blast counts. Overall, neither mutated STAG2, RAD21, SMC1A nor SMC3 displayed any significant, independent effect on clinical outcomes defined as complete remission, event-free, relapse-free or overall survival. However, we found almost complete mutual exclusivity of genetic alterations of individual cohesin subunits. This mutual exclusivity may be the basis for therapeutic strategies via synthetic lethality in cohesin mutated AML. Nature Publishing Group UK 2023-01-24 /pmc/articles/PMC9873811/ /pubmed/36693840 http://dx.doi.org/10.1038/s41408-023-00790-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Eckardt, Jan-Niklas
Stasik, Sebastian
Röllig, Christoph
Sauer, Tim
Scholl, Sebastian
Hochhaus, Andreas
Crysandt, Martina
Brümmendorf, Tim H.
Naumann, Ralph
Steffen, Björn
Kunzmann, Volker
Einsele, Hermann
Schaich, Markus
Burchert, Andreas
Neubauer, Andreas
Schäfer-Eckart, Kerstin
Schliemann, Christoph
Krause, Stefan W.
Herbst, Regina
Hänel, Mathias
Hanoun, Maher
Kaiser, Ulrich
Kaufmann, Martin
Rácil, Zdenek
Mayer, Jiri
Cerqueira, Tiago
Kroschinsky, Frank
Berdel, Wolfgang E.
Serve, Hubert
Müller-Tidow, Carsten
Platzbecker, Uwe
Baldus, Claudia D.
Schetelig, Johannes
Siepmann, Timo
Bornhäuser, Martin
Middeke, Jan Moritz
Thiede, Christian
Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome
title Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome
title_full Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome
title_fullStr Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome
title_full_unstemmed Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome
title_short Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome
title_sort alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9873811/
https://www.ncbi.nlm.nih.gov/pubmed/36693840
http://dx.doi.org/10.1038/s41408-023-00790-1
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