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

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.
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.
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.
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.

白血病是一类异质性血液系统恶性肿瘤，大体可分为髓系（myeloid）与淋巴系（lymphoid）两大亚型，二者均具有独特的分子与临床特征。本研究旨在识别髓系与淋巴系白血病的谱系特异性分子脆弱点，并以此指导靶向治疗与合理药物重定位。

本研究对19组GEO数据集进行了荟萃分析，纳入了来自急性与慢性白血病亚型的超2600份样本。研究首先识别出差异表达基因（differentially expressed genes, DEGs），并对其进行功能富集分析与蛋白质相互作用（protein-protein interaction, PPI）网络分析；随后采用LINCS L1000CDS2数据库筛选枢纽基因以用于药物重定位。最终通过分子对接、动力学模拟以及MTT实验，在多种白血病细胞系中对候选化合物进行了验证。

本研究共识别出髓系白血病相关差异表达基因269个，淋巴系白血病相关差异表达基因316个。富集分析结果显示，DNA复制与细胞周期通路是髓系白血病的驱动通路，而淋巴系白血病则与转录调控及免疫信号通路密切相关。筛选得到的枢纽基因包括CCNB1、KIF11、EGFR与JUN。经药物重定位筛选得到SN-38与C646两种极具潜力的候选化合物，分子对接与分子动力学模拟结果证实，二者可与IGF1R及RBP2紧密结合。MTT实验结果显示，二者具有显著的时间与剂量依赖性细胞毒性。

本整合研究策略将转录组学与药物发现及临床前验证相结合，成功揭示了谱系特异性的分子脆弱点，为白血病的精准治疗与合理药物重定位提供了理论框架。