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Background: Several prognostic biomarkers have been validated for acute myeloid leukemia (AML), a heterogeneous hematopoietic malignancy. However, the factors associated with the cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) in real-world patients with AML have not been well defined., Methods: This study examined clinical and mutational data of 246 patients with newly diagnosed AML who received the traditional "3 ​+ ​7" regimen in PLA General Hospital from January 2008 to August 2020. Factors associated with CIR and LFS in patients newly diagnosed with AML were analyzed using next-generation sequencing., Results: Additional sex combs-like 1 ( ASXL1 ) and Serine/arginine-rich splicing factor 2 ( SRSF2 ) mutations were found to be associated with an increased risk of CIR and a reduced LFS in univariate analysis, while only SRSF2 mutations were associated with these factors in the multivariate analysis. Hyperleukocytosis maintained an independent effect on LFS in the multivariate analysis. Hematopoietic stem cell transplantation conferred a significant prognostic benefit on both CIR and LFS in our cohort. Furthermore, we validated the risk classification of patients with AML receiving traditional induction regimens across a broad age range. Based on next-generation sequencing results, we concluded that SRSF2 mutations were predictive of an increased risk of relapse, inferior LFS rates, and non-relapse mortality in patients with newly diagnosed AML., Conclusion: These findings indicate that patients with SRSF2 mutations might not benefit from the conventional "3 ​+ ​7" regimen. Our results may help in developing molecular stratification strategies and could guide treatment decisions for patients with newly diagnosed AML., Competing Interests: We declare that we have no financial and personal relationships with other people or Acornmed Biotechnology Co., Ltd that can inappropriately influence our work., (© 2022 Published by Elsevier B.V. on behalf of Chinese Medical Association (CMA).)