Mutated IKZF1 is an independent marker of adverse risk in acute myeloid leukemia

Abstract

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.

Fig. 1. Localizations of deduced amino acid changes and co-mutational profile of IKZF1 alterations in acute myeloid leukemia.

IKZF1 was mutated in 45/1606 AML patients. Schematic representation of the IKZF1 protein (A). IKZF1 has four N-terminal zinc finger (ZF) domains (blue) and two C-terminal ZF domains (green). The x-axis represents amino acid positions with specific annotations for amino acids forming the ZF domains. The hotspot mutation p.N159S was present in 42.2% of cases (n = 19). This domain and locus are highly conserved across species (B). Median variant allele frequency (VAF) for IKZF1 was 44% (C). Alterations were predominantly missense rather than truncating mutations (C). AML patients bearing mutated IKZF1 had a median of four overall mutations (C). Compared to wildtype patients, patients with altered IKZF1 harbored significantly higher rates of co-occurring alterations in RUNX1, GATA2, KRAS, KIT, SF3B1, and ETV6 while co-occurrence of NPM1, FLT3-ITD, and TET2 were rare (D). For detailed information on frequency and statistical significance of associated co-mutations, please see Table S2.

Fig. 2. Survival analysis regarding IKZF1 mutation status in acute myeloid leukemia.

Survival analysis using Kaplan–Meier estimators and the log-rank test. First, differences in survival times were analyzed comparing mutated (mut.) vs. wildtype (wt) IKZF1 (A–C). AML patients with mut. IKZF1 (red) show significantly decreased event-free (A), relapse-free (B), and overall survival (C) compared to AML patients with wt IKZF1 (blue). The hotspot mutation N159S confers decreased event-free (D), relapse-free (E), and overall survival (F) while patients harboring non-N159S IKZF1 (other) alterations find themselves in between IKZF1-N159S and wt patients with regard to survival times. Survival times in months. Boldface indicates statistical significance (p < 0.05).