Differential Implications of CSF3R Mutations in t(8;21) and CEBPA Double Mutated Acute Myeloid Leukemia

Abstract

BackgroundFew data are available exploring mutations of the colony-stimulating factor 3 receptor (CSF3R) in acute myeloid leukemia (AML) in an all-round and systematic manner. The purpose of this study was to analyze the CSF3R mutations (CSF3Rmut) in AML with recurrent genetic abnormalities for potential synergistic pathomechanism. Patients and MethodsWe retrospectively screened 1102 adult de novo AML patients with available next-generation sequencing (NGS) information on 132 genes related to hematologic disorders. The χ2, Mann-Whitney U tests were used to analyze their associations with clinicopathologic characteristics, and a propensity score matching (PSM) followed by Kaplan-Meier method was applied to measure their prognostic effects. ResultsOverall, CSF3Rmut were detected in 40 (3.6%) of 1102 patients with adult de novo AML. CSF3Rmut were predominantly enriched in AML with the CEBPA double mutations (CEBPAdm) (16/122, 13.1%), t(8;21) (12/186, 6.5%) and mutated RUNX1 (3/50, 6.0%), respectively. The CSF3Rmut loci and types differed according to AML subtypes, with frameshift-indels and premature stop confined in the t(8;21) AML [10/12 (83.3%)], and missense recurrently aggregated in the CEBPAdm AML [16/16 (100%)]. Cases with CSF3Rmut had a lower WBC count versus those with CSF3R wild-type (CSF3Rwt) in the t(8;21) AML cohort, with a borderline significance [median 5.45 (range 0.94-20.30) × 109/L) vs. 8.80 (range 0.96-155.00) × 109/L, P = .046]. CSF3Rmut were non-significantly associated with higher WBC counts [median 33.6 (range 6.8-287.6) × 109/L vs. 18.1 (range 1.7-196.0) × 109/L, P = .156] and significantly with lower immunophenotypic CD15 positivity [0/8 (0%) vs. 44/80 (55%), P = .009] as compared to CSF3Rwt in the CEBPAdm AML cohort. After propensity score matching followed by Kaplan-Meier analysis, CSF3Rmut cases had comparable disease-free survival (DFS) and overall survival (OS) to those with CSF3Rwt (P = .607 and P = .842, respectively) in the t(8;21) AML cohort. By contrast, CSF3Rmut showed an inclination towards inferior DFS compared to CSF3Rwt in the CEBPAdm AML cohort [median DFS 19.8 (95%CI 3.1-36.5) months vs. not reached (NR), P = .086]. No significant difference was found for OS between CSF3Rmut and CSF3Rwt cases (P = .943). ConclusionWe concluded that CSF3Rmut were frequently enriched in patients with t(8;21) and CEBPAdm subtypes among AML, but showed divergent clinicopathologic features, mutation loci and types and differing prognostic aspects.