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The use of FMS-like tyrosine kinase 3 (FLT3) as a crucial target for kinase inhibitors is well established, but its association with immune infiltration remains unclear. This study aimed to explore the relationship between FLT3 mutations and immune checkpoint molecules (ICMs) in patients with acute myeloid leukemia (AML).

The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were used to identify the ICMs associated with FLT3 mutations. A Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were conducted to analyze the signaling pathways related to the ICMs. The single-sample GSEA (ssGSEA), Cibersort, and estimate algorithms were used to assess immune cell infiltration in AML.

Absent in melanoma 2 (AIM2) exhibits elevated expression levels in AML patients harboring FLT3 mutation, contributing significantly to the progress of AML and establishing of an immunosuppressive microenvironment. AIM2 expression significantly correlated with sensitivity of clinically relevant drugs in ex vivo assays of AML. Additionally, AIM2 demonstrates substantial prognostic value and holds promise as a prospective immunotherapeutic target for AML. Our findings indicate a significant correlation between AIM2 and immune infiltration in AML cases, potentially affecting the presence of neutrophils, macrophages, effector memory T cells (Tem), and monocytes. Furthermore, AIM2 is closely linked to various signaling pathways, such as immune cytokine release, immune antigen presentation, and inflammasome signaling, which could play a role in immune cell enrichment in AML.

Our study identified AMI2 as an ICM linked to FLT3 mutations. AMI2 may be involved in the activation of suppressive immune cell populations, such as macrophages, neutrophils, and monocytes. AIM2 could serve as a promising immunotherapeutic target for combination therapy with FLT3 inhibitors in AML.

Acute lymphoblastic leukemia (ALL) is a disease of lymphocyte origin predominantly diagnosed in children. While its 5-year survival rate is high, resistance to chemotherapy drugs is still an obstacle. Our aim is to determine differentially expressed genes (DEGs) related to Asparaginase, Daunorubicin, Prednisolone, and Vincristine resistance and identify potential inhibitors via docking. Three datasets were accessed from the Gene Expression Omnibus database; GSE635, GSE19143, and GSE22529. The microarray data was analyzed using R4.2.0 and Bioconductor packages, and pathway and protein-protein interaction analysis were performed. We identified 1294 upregulated DEGs, with 12 genes consistently upregulated in all four resistant groups. KEGG analysis revealed an association with the PI3K-Akt pathway. Among DEGs, 33 hub genes including MDM2 and USP7 were pinpointed. Within common genes, CLDN9 and HS3ST3A1 were subjected to molecular docking against 3556 molecules. Following ADMET analysis, three drugs emerged as potential inhibitors: Flunarizine, Talniflumate, and Eltrombopag. Molecular dynamics analysis for HS3ST3A1 indicated all candidates had the potential to overcome drug resistance, Eltrombopag displaying particularly promising results. This study promotes a further understanding of drug resistance in ALL, introducing novel genes for consideration in diagnostic screening. It also presents potential inhibitor candidates to tackle drug resistance through repurposing.