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

• Authors: ECKARDT Jan-Niklas; STASIK Sebastian; ROLLIG Christoph; SAUER Tim; SCHOLL Sebastian; HOCHHAUS Andreas; CRYSANDT Martina; BRUEMMENDORF Tim H; NAUMANN Ralph; STEFFEN Bjoern; KUNZMANN Volker; EINSELE Hermann; SCHAICH Markus; BURCHERT Andreas; NEUBAUER Andreas; SCHAEFER-ECKART Kerstin; SCHLIEMANN Christoph; KRAUSE Stefan W; HERBST Regina; HAENEL Mathias; HANOUN Maher; KAISER Ulrich; KAUFMANN Martin; RÁČIL Zdeněk; MAYER Jiří; CERQUEIRA Tiago; KROSCHINSKY Frank; BERDEL Wolfgang E; SERVE Hubert; MUELLER-TIDOW Carsten; PLATZBECKER Uwe; BALDUS Claudia D; SCHETELIG Johannes; SIEPMANN Timo; BORNHAEUSER Martin; MIDDEKE Jan Moritz; THIEDE Christian
• Year of publication: 2023
• Type: Article in Periodical
• Magazine / Source: Blood Cancer Journal
• MU Faculty or unit: Faculty of Medicine
• Web: https://www.nature.com/articles/s41408-023-00790-1
• Doi: http://dx.doi.org/10.1038/s41408-023-00790-1
• Keywords: acute myeloid leukemia; cohesin complex genes
• 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.