SRSF2 mutations drive daunorubicin resistance in acute myeloid leukemia via THBS1 stabilization

TL;DR

This study shows that SRSF2 mutations in acute myeloid leukemia reduce the effectiveness of daunorubicin chemotherapy by stabilizing THBS1 mRNA and altering splicing patterns.

Contribution

The study identifies SRSF2 mutations as drivers of daunorubicin resistance in AML and proposes PDGFB pathway inhibition as a potential treatment strategy.

Findings

SRSF2 mutations decrease AML patient survival and reduce sensitivity to daunorubicin and homoharringtonine.

SRSF2 mutations stabilize THBS1 mRNA and alter ETV7 splicing, contributing to drug resistance.

Combining PDGFB pathway inhibitors with daunorubicin enhances cytotoxicity in mutant AML cells.

Abstract

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 SRSF2 mutations in AML and their impact on chemotherapeutic drug sensitivity.

The prognostic value of SRSF2 mutations was analyzed in AML patients. SRSF2-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.

Clinical analysis revealed that SRSF2 mutations decreased the survival of AML patients. In vitro experiments demonstrated that SRSF2 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 SRSF2-mutant AML. Mechanistically, SRSF2 mutation impaired the interaction between the SRSF2 protein and THBS1 mRNA, prolonging the THBS1 mRNA half-life and enhancing its translation efficiency, leading to THBS1 protein accumulation. Additionally, the mutation altered the splicing pattern of ETV7 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.

SRSF2 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.

The online version contains supplementary material available at 10.1186/s13046-026-03649-y.

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