Blood Cancer Journal (Jan 2023)
Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome
- Jan-Niklas Eckardt,
- Sebastian Stasik,
- Christoph Röllig,
- Tim Sauer,
- Sebastian Scholl,
- Andreas Hochhaus,
- Martina Crysandt,
- Tim H. Brümmendorf,
- Ralph Naumann,
- Björn Steffen,
- Volker Kunzmann,
- Hermann Einsele,
- Markus Schaich,
- Andreas Burchert,
- Andreas Neubauer,
- Kerstin Schäfer-Eckart,
- Christoph Schliemann,
- Stefan W. Krause,
- Regina Herbst,
- Mathias Hänel,
- Maher Hanoun,
- Ulrich Kaiser,
- Martin Kaufmann,
- Zdenek Rácil,
- Jiri Mayer,
- Tiago Cerqueira,
- Frank Kroschinsky,
- Wolfgang E. Berdel,
- Hubert Serve,
- Carsten Müller-Tidow,
- Uwe Platzbecker,
- Claudia D. Baldus,
- Johannes Schetelig,
- Timo Siepmann,
- Martin Bornhäuser,
- Jan Moritz Middeke,
- Christian Thiede
Affiliations
- Jan-Niklas Eckardt
- Department of Internal Medicine I, University Hospital Carl Gustav Carus
- Sebastian Stasik
- Department of Internal Medicine I, University Hospital Carl Gustav Carus
- Christoph Röllig
- Department of Internal Medicine I, University Hospital Carl Gustav Carus
- Tim Sauer
- German Cancer Research Center (DKFZ) and Medical Clinic V, University Hospital Heidelberg
- Sebastian Scholl
- Department of Internal Medicine II, Jena University Hospital
- Andreas Hochhaus
- Department of Internal Medicine II, Jena University Hospital
- Martina Crysandt
- Department of Hematology, Oncology, Hemostaseology, and Cell Therapy, University Hospital RWTH Aachen
- Tim H. Brümmendorf
- Department of Hematology, Oncology, Hemostaseology, and Cell Therapy, University Hospital RWTH Aachen
- Ralph Naumann
- Medical Clinic III, St. Marien-Hospital Siegen
- Björn Steffen
- Medical Clinic II, University Hospital Frankfurt
- Volker Kunzmann
- Medical Clinic and Policlinic II, University Hospital Würzburg
- Hermann Einsele
- Medical Clinic and Policlinic II, University Hospital Würzburg
- Markus Schaich
- Department of Hematology, Oncology and Palliative Care, Rems-Murr-Hospital Winnenden
- Andreas Burchert
- Department of Hematology, Oncology and Immunology, Philipps-University-Marburg
- Andreas Neubauer
- Department of Hematology, Oncology and Immunology, Philipps-University-Marburg
- Kerstin Schäfer-Eckart
- Department of Internal Medicine V, Paracelsus Medizinische Privatuniversität and University Hospital Nurnberg
- Christoph Schliemann
- Department of Medicine A, University Hospital Münster
- Stefan W. Krause
- Medical Clinic V, University Hospital Erlangen
- Regina Herbst
- Medical Clinic III, Chemnitz Hospital AG
- Mathias Hänel
- Medical Clinic III, Chemnitz Hospital AG
- Maher Hanoun
- Department of Hematology, University Hospital Essen
- Ulrich Kaiser
- Medical Clinic II, St. Bernward Hospital
- Martin Kaufmann
- Department of Hematology, Oncology and Palliative Care, Robert-Bosch-Hospital
- Zdenek Rácil
- Department of Internal Medicine, Hematology and Oncology, Masaryk University Hospital
- Jiri Mayer
- Department of Internal Medicine, Hematology and Oncology, Masaryk University Hospital
- Tiago Cerqueira
- Division of Health Care Sciences, Dresden International University
- Frank Kroschinsky
- Department of Internal Medicine I, University Hospital Carl Gustav Carus
- Wolfgang E. Berdel
- Department of Medicine A, University Hospital Münster
- Hubert Serve
- Medical Clinic II, University Hospital Frankfurt
- Carsten Müller-Tidow
- German Cancer Research Center (DKFZ) and Medical Clinic V, University Hospital Heidelberg
- Uwe Platzbecker
- Medical Clinic I Hematology and Celltherapy, University Hospital Leipzig
- Claudia D. Baldus
- Department of Internal Medicine, University Hospital Kiel
- Johannes Schetelig
- Department of Internal Medicine I, University Hospital Carl Gustav Carus
- Timo Siepmann
- Division of Health Care Sciences, Dresden International University
- Martin Bornhäuser
- Department of Internal Medicine I, University Hospital Carl Gustav Carus
- Jan Moritz Middeke
- Department of Internal Medicine I, University Hospital Carl Gustav Carus
- Christian Thiede
- Department of Internal Medicine I, University Hospital Carl Gustav Carus
- DOI
- https://doi.org/10.1038/s41408-023-00790-1
- Journal volume & issue
-
Vol. 13,
no. 1
pp. 1 – 9
Abstract
Abstract 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.
