Genetic lesions of IKZF1 are frequent events and well-established markers of adverse risk in acute lymphoblastic leukemia. However, their function in the pathophysiology and impact on patient outcome in acute myeloid leukemia (AML) remains elusive. In a multicenter cohort of 1606 newly diagnosed and intensively treated adult AML patients, we found IKZF1 alterations in 45 cases with a mutational hotspot at N159S. AML with mutated IKZF1 was associated with alterations in RUNX1, GATA2, KRAS, KIT, SF3B1, and ETV6, while alterations of NPM1, TET2, FLT3-ITD, and normal karyotypes were less frequent. The clinical phenotype of IKZF1-mutated AML was dominated by anemia and thrombocytopenia. In both univariable and multivariable analyses adjusting for age, de novo and secondary AML, and ELN2022 risk categories, we found mutated IKZF1 to be an independent marker of adverse risk regarding complete remission rate, event-free, relapse-free, and overall survival. The deleterious effects of mutated IKZF1 also prevailed in patients who underwent allogeneic hematopoietic stem cell transplantation (n = 519) in both univariable and multivariable models. These dismal outcomes are only partially explained by the hotspot mutation N159S. Our findings suggest a role for IKZF1 mutation status in AML risk modeling.

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 5 Paracelsus Medizinische Privatuniversität and University Hospital Nuremberg Nuremberg 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

DKMS Clinical Trials Unit Dresden Germany

Dresden Concept Genome Center Center for Molecular and Cellular Bioengineering Technische Universität Dresden Dresden Germany

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

German Consortium for Translational Cancer Research DKFZ Heidelberg Germany

Klinik für Innere Medizin 2 Jena University Hospital Jena 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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