SRSF2 mutations drive daunorubicin resistance in acute myeloid leukemia via THBS1 stabilization.
1/5 보강
[BACKGROUND] Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the uncontrolled growth of immature myeloid cells, often with a poor prognosis due to therapy resista
APA
Ye W, Wu X, et al. (2026). SRSF2 mutations drive daunorubicin resistance in acute myeloid leukemia via THBS1 stabilization.. Journal of experimental & clinical cancer research : CR, 45(1). https://doi.org/10.1186/s13046-026-03649-y
MLA
Ye W, et al.. "SRSF2 mutations drive daunorubicin resistance in acute myeloid leukemia via THBS1 stabilization.." Journal of experimental & clinical cancer research : CR, vol. 45, no. 1, 2026.
PMID
41618430 ↗
Abstract 한글 요약
[BACKGROUND] Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the uncontrolled growth of immature myeloid cells, often with a poor prognosis due to therapy resistance. This study investigated the prognostic significance of mutations in AML and their impact on chemotherapeutic drug sensitivity.
[METHODS] The prognostic value of mutations was analyzed in AML patients. -mutant cell models were generated via lentiviral transduction for drug sensitivity testing. Xenograft mice were used to assess daunorubicin (DNR) efficacy. Mechanistic studies included transcriptomics, splicing analysis, mRNA stability, polysome profiling, RNA immunoprecipitation, and metabolic assays to identify targetable resistance pathways.
[RESULTS] Clinical analysis revealed that mutations decreased the survival of AML patients. experiments demonstrated that mutation reduced the sensitivity of AML cells to drugs such as DNR and homoharringtonine but did not affect the response to venetoclax. In mouse models, DNR treatment was effective against wild-type AML but showed significantly reduced efficacy in suppressing tumors and improving survival in -mutant AML. Mechanistically, mutation impaired the interaction between the protein and mRNA, prolonging the mRNA half-life and enhancing its translation efficiency, leading to THBS1 protein accumulation. Additionally, the mutation altered the splicing pattern of and upregulated its expression, potentially mediating DNR resistance. Metabolic analysis revealed that mutant cells presented increased spare respiratory capacity, supporting energy demands under stress. Inhibition of the PDGFB pathway (CP-673451) synergistically enhanced the cytotoxic effect of DNR on mutant cells.
[CONCLUSIONS] mutations promoted DNR resistance through multiple mechanisms, and targeted combination therapy with PDGFB pathway inhibitors may represent a novel strategy to improve therapeutic outcomes in patients with mutations.
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s13046-026-03649-y.
[METHODS] The prognostic value of mutations was analyzed in AML patients. -mutant cell models were generated via lentiviral transduction for drug sensitivity testing. Xenograft mice were used to assess daunorubicin (DNR) efficacy. Mechanistic studies included transcriptomics, splicing analysis, mRNA stability, polysome profiling, RNA immunoprecipitation, and metabolic assays to identify targetable resistance pathways.
[RESULTS] Clinical analysis revealed that mutations decreased the survival of AML patients. experiments demonstrated that mutation reduced the sensitivity of AML cells to drugs such as DNR and homoharringtonine but did not affect the response to venetoclax. In mouse models, DNR treatment was effective against wild-type AML but showed significantly reduced efficacy in suppressing tumors and improving survival in -mutant AML. Mechanistically, mutation impaired the interaction between the protein and mRNA, prolonging the mRNA half-life and enhancing its translation efficiency, leading to THBS1 protein accumulation. Additionally, the mutation altered the splicing pattern of and upregulated its expression, potentially mediating DNR resistance. Metabolic analysis revealed that mutant cells presented increased spare respiratory capacity, supporting energy demands under stress. Inhibition of the PDGFB pathway (CP-673451) synergistically enhanced the cytotoxic effect of DNR on mutant cells.
[CONCLUSIONS] mutations promoted DNR resistance through multiple mechanisms, and targeted combination therapy with PDGFB pathway inhibitors may represent a novel strategy to improve therapeutic outcomes in patients with mutations.
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s13046-026-03649-y.
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