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

Few 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 (CSF3R_mut) in AML with recurrent genetic abnormalities for potential synergistic pathomechanism.

We 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.

Overall, CSF3R_mut were detected in 40 (3.6%) of 1102 patients with adult de novo AML. CSF3R_mut were predominantly enriched in AML with the CEBPA double mutations (CEBPA_dm) (16/122, 13.1%), t(8;21) (12/186, 6.5%) and mutated RUNX1 (3/50, 6.0%), respectively. The CSF3R_mut 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 CEBPA_dm AML [16/16 (100%)]. Cases with CSF3R_mut had a lower WBC count versus those with CSF3R wild-type (CSF3R_wt) 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]. CSF3R_mut 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 CSF3R_wt in the CEBPA_dm AML cohort. After propensity score matching followed by Kaplan-Meier analysis, CSF3R_mut cases had comparable disease-free survival (DFS) and overall survival (OS) to those with CSF3R_wt (P = .607 and P = .842, respectively) in the t(8;21) AML cohort. By contrast, CSF3R_mut showed an inclination towards inferior DFS compared to CSF3R_wt in the CEBPA_dm 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 CSF3R_mut and CSF3R_wt cases (P = .943).

We concluded that CSF3R_mut were frequently enriched in patients with t(8;21) and CEBPA_dm subtypes among AML, but showed divergent clinicopathologic features, mutation loci and types and differing prognostic aspects.