Multi-omics integration reveals potential stage-specific druggable targets in T-cell acute lymphoblastic leukemia

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外文摘要：T-cell acute lymphoblastic leukemia(T-ALL),a heterogeneous hematological malig-nancy,is caused by the developmental arrest of normal T-cell progenitors.The development of targeted therapeutic regimens is impeded by poor knowledge of the stage-specific aberrances in this disease.In this study,we performed multi-omics integration analysis,which included mRNA expression,chromatin accessibility,and gene-dependency database analyses,to iden-tify potential stage-specific druggable targets and repositioned drugs for this disease.This mul-ti-omics integration helped identify 29 potential pathological genes for T-ALL.These genes exhibited tissue-specific expression profiles and were enriched in the cell cycle,hematopoietic stem cell differentiation,and the AMPK signaling pathway.Of these,four known druggable tar-gets(CDK6,TUBA1A,TUBB,and TYMS)showed dysregulated and stage-specific expression in malignant T cells and may serve as stage-specific targets in T-ALL.The TUBA1A expression level was higher in the early T cell precursor(ETP)-ALL cells,while TUBB and TYMS were mainly highly expressed in malignant T cells arrested at the CD4 and CD8 double-positive or single-pos-itive stage.CDK6 exhibited a U-shaped expression pattern in malignant T cells along the naive to maturation stages.Furthermore,mebendazole and gemcitabine,which target TUBA1A and TYMS,respectively,exerted stage-specific inhibitory effects on T-ALL cell lines,indicating their potential stage-specific antileukemic role in T-ALL.Collectively,our findings might aid in identifying potential stage-specific druggable targets and are promising for achieving more precise therapeutic strategies for T-ALL.

外文关键词：

Multi-omicsStage-specific druggable targetsTargeted therapeutic strategiesT-cell acute lymphoblastic leukemiaDrug repositioning

作者：

Zijun Yan、Jie Xia、Ziyang Cao、Hongyang Zhang、Jinxia Wang、Tienan Feng、Yi Shu、Lin Zou

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作者单位：

Clinical Research Unit,Shanghai Children's Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200062,China

Institute of Pediatric Infection,Immunity,and Critical Care Medicine,Shanghai Jiao Tong University School of Medicine,Shanghai 200062,China

Bioinformatics and BioMedical Bigdata Mining Laboratory,School of Big Health,Guizhou Medical University,Guiyang,Guizhou 554300,China

Clinical Research Institute,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

Center for Clinical Molecular Laboratory Medicine of Children's Hospital of Chongqing Medical University,Chongqing 400014,China

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基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaChongqing Science and Technology Bureau Major Project,Chongqing,China

项目编号：

82070167818701268190019081802803cstc2020jcyjmsxmX0782

出版年：

2024

DOI：

10.1016/j.gendis.2023.03.022

基因与疾病(英文)

ISSN：

年,卷(期)：2024.11(5)