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.

Department of Hematology Oncology and Immunology Philipps University Marburg Marburg Germany

Department of Hematology Oncology and Palliative Care Rems Murr Hospital Winnenden Winnenden Germany

Department of Hematology Oncology and Palliative Care Robert Bosch Hospital Stuttgart Germany

Department of Hematology Oncology Hemostaseology and Cell Therapy University Hospital RWTH Aachen Aachen Germany

Department of Hematology University Hospital Essen Essen Germany

Department of Internal Medicine 1 University Hospital Carl Gustav Carus Dresden Germany

Department of Internal Medicine 2 Jena University Hospital Jena Germany

Department of Internal Medicine 5 Paracelsus Medizinische Privatuniversität and University Hospital Nurnberg Nurnberg Germany

Department of Internal Medicine Hematology and Oncology Masaryk University Hospital Brno Czech Republic

Department of Internal Medicine University Hospital Kiel Kiel Germany

Department of Medicine A University Hospital Münster Münster Germany

Department of Neurology University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany

Division of Health Care Sciences Dresden International University Dresden Germany

DKMS Clinical Trials Unit Dresden Germany

German Cancer Research Center and Medical Clinic 5 University Hospital Heidelberg Heidelberg Germany

German Consortium for Translational Cancer Research DKTK Heidelberg Germany

Medical Clinic 1 Hematology and Celltherapy University Hospital Leipzig Leipzig Germany

Medical Clinic 2 St Bernward Hospital Hildesheim Germany

Medical Clinic 2 University Hospital Frankfurt Frankfurt Germany

Medical Clinic 3 Chemnitz Hospital AG Chemnitz Germany

Medical Clinic 3 St Marien Hospital Siegen Siegen Germany

Medical Clinic 5 University Hospital Erlangen Erlangen Germany

Medical Clinic and Policlinic 2 University Hospital Würzburg Würzburg Germany

National Center for Tumor Disease Dresden Germany

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