Clinical profiling of AML1::ETO and KIT exon 17 mutation in pediatric AML by high-throughput drug sensitivity

The favorable prognosis of pediatric AML1::ETO acute myeloid leukemia (AML) is well-established, yet the impact of co-occurring KIT mutations-particularly in exon 17-on clinical outcomes and chemosensitivity remains incompletely defined.

We analyzed the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database comprising 957 pediatric AML patients to assess the clinical characteristics and prognosis of pediatric patients harboring AML1::ETO and KIT mutation using Kaplan-Meier survival analysis and Cox proportional hazards models. Subsequently, we performed experimental validation using bone marrow samples from 16 pediatric AML patients at Shenzhen Children's Hospital by high-throughput drug sensitivity (HDS) screening against therapeutic agents and whole transcriptome sequencing analysis of significant genes. Functional enrichment analysis of these differential expression genes was carried out by Gene Ontology.

Analysis from the TARGET database revealed that while AML1::ETO AML generally carries a favorable prognosis, concomitant KIT exon 17 mutations significantly attenuate this survival advantage. Exploratory experimental validation in a limited cohort of AML1::ETO and KIT exon 17 mutation patients suggested a potential trend of broad drug resistance such as cytarabine and daunorubicin. Preliminary transcriptomic analysis identified upregulation of SOCS1, a negative regulator of the JAK-STAT pathway, as a potential feature of this resistant phenotype. Furthermore, elevated SOCS1 expression was associated with poor prognosis.

We conclude that KIT mutations, especially exon 17, confer a high-risk phenotype in otherwise favorable pediatric AML1::ETO AML. Our exploratory data suggest this may be associated with a chemoresistant profile, potentially driven by SOCS1-associated JAK-STAT dysregulation. These findings highlight the necessity of refined risk stratification based on KIT exon profiling and support targeting the SOCS1/JAK-STAT axis to overcome therapy resistance.