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Full Length Article | Open Access

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

Zijun Yana,b, Jie Xiae, Ziyang Caoa,b, Hongyang Zhanga,b, Jinxia Wanga,b, Tienan Fenga,d, Yi Shuc( ), Lin Zoua,b,c( )
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
Center for Clinical Molecular Laboratory Medicine of Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Bioinformatics and BioMedical Bigdata Mining Laboratory, School of Big Health, Guizhou Medical University, Guiyang, Guizhou 554300, China

Peer review under responsibility of Chongqing Medical University.

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Abstract

T-cell acute lymphoblastic leukemia (T-ALL), a heterogeneous hematological malignancy, 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 identify potential stage-specific druggable targets and repositioned drugs for this disease. This multi-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 targets (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-positive stage. CDK6 exhibited a U-shaped expression pattern in malignant T cells along the naïve 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.

Keywords

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

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Genes & Diseases
Volume 11 Issue 5,
September 2024
Article number: 100949
DOI: 10.1016/j.gendis.2023.03.022
Cite this article:
Yan Z, Xia J, Cao Z, et al. Multi-omics integration reveals potential stage-specific druggable targets in T-cell acute lymphoblastic leukemia. Genes & Diseases, 2024, 11(5): 100949. https://doi.org/10.1016/j.gendis.2023.03.022

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Received: 20 October 2022
Accepted: 11 March 2023
Published: 26 April 2023
© 2023 The Authors.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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