Lineage-specific transcriptomic signatures and therapeutic target discovery in myeloid and lymphoid leukemias.

AIM: Leukemias are heterogenous hematologic malignancies broadly classified into myeloid and lymphoid lineages, each with distinct molecular and clinical features. Here we aime to identify lineage-specific molecular vulnerabilities in myeloid and lymphoid leukemias and use them to guide targeted therapy and rational drug repurposing.

MATERIALS & METHODS: A meta-analysis of 19 GEO datasets comprising >2,600 samples from acute and chronic leukemia subtypes was performed. Differentially expressed genes (DEGs) were identified and subjected to functional enrichment and protein-protein interaction (PPI) network analyses. Hub genes were identified for drug repurposing using the LINCS L1000CDS2. Candidate compounds were validated by performing molecular docking, dynamics simulations and MTT assays on multiple leukemia cell lines.

RESULTS: 269 DEGs in myeloid and 316 DEGs in lymphoid leukemias were identified. Enrichment analysis showed that DNA replication and cell cycle pathways drive myeloid leukemias, while lymphoid leukemias are associated with transcriptional regulation and immune signaling. Hub genes included CCNB1, KIF11, EGFR and JUN. SN-38 and C646 were identified as promising candidates from drug repurposing. Docking and molecular dynamics simulations confirmed strong binding to IGF1R and RBP2. MTT assays revealed significant, time- and dose-dependent cytotoxicity.

CONCLUSION: This integrative approach links transcriptomics with drug discovery and preclinical validation. Lineage-specific vulnerabilities were uncovered, providing a framework for precision therapy and rational drug repurposing in leukemia.