Acute myeloid leukemia(AML)is an aggressive hematologic malignancy characterized by poor clinical outcomes,frequently exacerbated by mutations in the FMS-like tyrosine kinase 3(FLT3)gene.Although FLT3 inhibitors(FLT3i...Acute myeloid leukemia(AML)is an aggressive hematologic malignancy characterized by poor clinical outcomes,frequently exacerbated by mutations in the FMS-like tyrosine kinase 3(FLT3)gene.Although FLT3 inhibitors(FLT3i)have emerged as promising therapeutic agents,the absence of molecular biomarkers to predict FLT3i response remains a critical limitation in clinical practice.In this study,we performed a comprehensive multi-omics analysis integrating transcriptomic,proteomic,and pharmacogenomic data from the Beat AML cohort,the Cancer Cell Line Encyclopedia(CCLE),and the PXD023201 repository to elucidate the molecular consequences of FLT3 mutations in AML.Our analysis revealed significant differences in RNA and protein expression profiles between FLT3-mutant and wild-type AML cases,with a particularly striking association between FLT3 mutations and immune suppression.We further evaluated the drug sensitivity of FLT3-mutant patients to 3 FDA-approved FLT3i,gilteritinib,midostaurin,and quizartinib,and observed heightened sensitivity in FLT3-mutant cohorts,accompanied by the activation of immune-related pathways in treatment-responsive groups.These findings suggest a potential synergy between FLT3i efficacy and immune activation.Through rigorous bioinformatic analysis,we identified 3 candidate biomarkers:CD36,SASH1,and NIBAN2,associated with FLT3i sensitivity.These biomarkers were consistently upregulated in favorable prognostic subgroups and demonstrated strong correlations with immune activation pathways.The identification of CD36,SASH1,and NIBAN2 as predictive biomarkers offers a novel toolset for stratifying FLT3i response and prognosis.展开更多
基金supported by grants from the CAMS Innovation Fund for Medical Science(2023-I2M-3-014 to H.W.,2023-I2M-2-007 to H.W.,2021-I2M-1-073 to H.W.)the National Natural Science Foundation of China(82270236 to H.W.,82341080 to H.W.,82400271 to M.N.,82273217 to L.S.)+2 种基金the Fundamental Research Funds for the Central Universities,Peking Union Medical College(3332024200 to M.N.)the distinguished Young Scholars of Tianjin(22JCJQJC00090 to H.W.)the Tianjin Municipal Science and Technology Commission Grant(22JCQNJC00040 to L.S.).
文摘Acute myeloid leukemia(AML)is an aggressive hematologic malignancy characterized by poor clinical outcomes,frequently exacerbated by mutations in the FMS-like tyrosine kinase 3(FLT3)gene.Although FLT3 inhibitors(FLT3i)have emerged as promising therapeutic agents,the absence of molecular biomarkers to predict FLT3i response remains a critical limitation in clinical practice.In this study,we performed a comprehensive multi-omics analysis integrating transcriptomic,proteomic,and pharmacogenomic data from the Beat AML cohort,the Cancer Cell Line Encyclopedia(CCLE),and the PXD023201 repository to elucidate the molecular consequences of FLT3 mutations in AML.Our analysis revealed significant differences in RNA and protein expression profiles between FLT3-mutant and wild-type AML cases,with a particularly striking association between FLT3 mutations and immune suppression.We further evaluated the drug sensitivity of FLT3-mutant patients to 3 FDA-approved FLT3i,gilteritinib,midostaurin,and quizartinib,and observed heightened sensitivity in FLT3-mutant cohorts,accompanied by the activation of immune-related pathways in treatment-responsive groups.These findings suggest a potential synergy between FLT3i efficacy and immune activation.Through rigorous bioinformatic analysis,we identified 3 candidate biomarkers:CD36,SASH1,and NIBAN2,associated with FLT3i sensitivity.These biomarkers were consistently upregulated in favorable prognostic subgroups and demonstrated strong correlations with immune activation pathways.The identification of CD36,SASH1,and NIBAN2 as predictive biomarkers offers a novel toolset for stratifying FLT3i response and prognosis.
