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

被引:0
作者
Yan, Zijun [1 ,2 ]
Xia, Jie [5 ]
Cao, Ziyang [1 ,2 ]
Zhang, Hongyang [1 ,2 ]
Wang, Jinxia [1 ,2 ]
Feng, Tienan [1 ,4 ]
Shu, Yi [3 ]
Zou, Lin [1 ,2 ,3 ]
机构
[1] Shanghai Jiao Tong Univ, Shanghai Childrens Hosp, Sch Med, Clin Res Unit, Shanghai 200062, Peoples R China
[2] Shanghai Jiao Tong Univ, Inst Pediat Infect Immun & Critical Care Med, Sch Med, Shanghai 200062, Peoples R China
[3] Chongqing Med Univ, Childrens Hosp, Ctr Clin Lab Med, Chongqing 400014, Peoples R China
[4] Shanghai Jiao Tong Univ, Clin Res Inst, Sch Med, Shanghai 200025, Peoples R China
[5] Guizhou Med Univ, Sch Big Hlth, Bioinformat & Biomed Bigdata Min Lab, Guiyang 554300, Guizhou, Peoples R China
基金
中国国家自然科学基金;
关键词
Multi-omics; Stage-specific druggable targets; Targeted therapeutic strategies; T-cell acute lymphoblastic leukemia; Drug repositioning; OF-FUNCTION MUTATIONS; CANCER; CHEMOTHERAPY; MEBENDAZOLE; TRANSCRIPT; ONCOGENES; PROMOTES; THERAPY; BENEFIT; ADULTS;
D O I
10.1016/j.gendis.2023.03.022
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 na & imath;<spacing diaeresis>veto 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. <feminine ordinal indicator> 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).
引用
收藏
页数:16
相关论文
共 50 条
[41]   T-cell acute lymphoblastic leukemia: promising experimental drugs in clinical development [J].
Thomas, Xavier .
EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2023, 32 (01) :37-52
[42]   Effect of Tissue Transglutaminase on Steroid Resistance in T-Cell Acute Lymphoblastic Leukemia [J].
Jung, Hyun Joo ;
Han, Eun Hee ;
Jang, In Keun ;
Yoon, Seung-Hyun ;
Park, Jun Eun .
ANTICANCER RESEARCH, 2019, 39 (11) :6165-6173
[43]   Bispecific T-cell engagers in childhood B-acute lymphoblastic leukemia [J].
Lyons, Kaylyn Utley ;
Gore, Lia .
HAEMATOLOGICA, 2024, 109 (06) :1668-1676
[44]   Single-cell sequencing reveals the origin and the order of mutation acquisition in T-cell acute lymphoblastic leukemia [J].
De Bie, Jolien ;
Demeyer, Sofie ;
Alberti-Servera, Llucia ;
Geerdens, Ellen ;
Segers, Heidi ;
Broux, Michael ;
De Keersmaecker, Kim ;
Michaux, Lucienne ;
Vandenberghe, Peter ;
Voet, Thierry ;
Boeckx, Nancy ;
Uyttebroeck, Anne ;
Cools, Jan .
LEUKEMIA, 2018, 32 (06) :1358-1369
[45]   TES and SLC40A1 as Potential Biomarkers for Predicting Survival in T-Cell Acute Lymphoblastic Leukemia [J].
Zeng, Xiangyou ;
Liu, Kaifan ;
Xu, Ruohao ;
Zhang, Lenghe ;
Lai, Peilong ;
Du, Xin ;
Weng, Jianyu .
ACTA HAEMATOLOGICA, 2025, 148 (02) :163-179
[46]   UTILIZATION OF 2 DIFFERENT T-CELL RECEPTORS BY T-CELL ACUTE LYMPHOBLASTIC LYMPHOMA AND LEUKEMIA [J].
GOUTTEFANGEAS, C ;
BENSUSSAN, A ;
BOUMSELL, L .
NOUVELLE REVUE FRANCAISE D HEMATOLOGIE, 1990, 32 (05) :337-340
[47]   Genomic characterization of pediatric T-cell acute lymphoblastic leukemia reveals novel recurrent driver mutations [J].
Spinella, Jean-Franois ;
Cassart, Pauline ;
Richer, Chantal ;
Saillour, Virginie ;
Ouimet, Manon ;
Langlois, Sylvie ;
St-Onge, Pascal ;
Sontag, Thomas ;
Healy, Jasmine ;
Minden, Mark D. ;
Sinnett, Daniel .
ONCOTARGET, 2016, 7 (40) :65485-65503
[48]   Multi-Omics Approach Reveals the Potential Core Vaccine Targets for the Emerging Foodborne Pathogen Campylobacter jejuni [J].
Cao, Hengchun ;
Xu, Hanxiao ;
Ning, Chunhui ;
Xiang, Li ;
Ren, Qiufang ;
Zhang, Tiantian ;
Zhang, Yusen ;
Gao, Rui .
FRONTIERS IN MICROBIOLOGY, 2021, 12
[49]   Potential roles of microRNA-29a in the molecular pathophysiology of T-cell acute lymphoblastic leukemia [J].
Oliveira, Lucila H. ;
Schiavinato, Josiane L. ;
Fraguas, Mariane S. ;
Lucena-Araujo, Antonio R. ;
Haddad, Rodrigo ;
Araujo, Amelia G. ;
Dalmazzo, Leandro F. ;
Rego, Eduardo M. ;
Covas, Dimas T. ;
Zago, Marco A. ;
Panepucci, Rodrigo A. .
CANCER SCIENCE, 2015, 106 (10) :1264-1277
[50]   Management of Recurrent Acute Lymphoblastic Leukemia With T-Cell Engagement: CAR T, BiTEs, and Beyond [J].
Park, Jae .
JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK, 2019, 17 (11) :1448-1450