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
  • [21] A Case of T-cell Acute Lymphoblastic Leukemia Relapsed As Myeloid Acute Leukemia
    Paganin, Maddalena
    Buldini, Barbara
    Germano, Giuseppe
    Seganfreddo, Elena
    di Meglio, Annamaria
    Magrin, Elisa
    Grillo, Francesca
    Pigazzi, Martina
    Rizzari, Carmelo
    Cazzaniga, Giovanni
    Khiabanian, Hossein
    Palomero, Teresa
    Rabadan, Raul
    Ferrando, Adolfo A.
    Basso, Giuseppe
    PEDIATRIC BLOOD & CANCER, 2016, 63 (09) : 1660 - 1663
  • [22] Incidence and survival of T-cell acute lymphoblastic leukemia in the United States
    Murthy, Guru Subramanian Guru
    Pondaiah, Satish Kumar
    Abedin, Sameem
    Atallah, Ehab
    LEUKEMIA & LYMPHOMA, 2019, 60 (05) : 1171 - 1178
  • [23] Strategies to Overcome Resistance Mechanisms in T-Cell Acute Lymphoblastic Leukemia
    Follini, Elena
    Marchesini, Matteo
    Roti, Giovanni
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2019, 20 (12):
  • [24] Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma
    Paolino, Jonathan
    Dimitrov, Boris
    Winger, Beth Apsel
    Sandoval-Perez, Angelica
    Rangarajan, Amith Vikram
    Ocasio-Martinez, Nicole
    Tsai, Harrison K.
    Li, Yuting
    Robichaud, Amanda L.
    Khalid, Delan
    Hatton, Charlie
    Gillani, Riaz
    Polonen, Petri
    Dilig, Anthony
    Gotti, Giacomo
    Kavanagh, Julia
    Adhav, Asmani A.
    Gow, Sean
    Tsai, Jonathan
    Li, Yen Der
    Ebert, Benjamin L.
    Van Allen, Eliezer M.
    Bledsoe, Jacob
    Kim, Annette S.
    Tasian, Sarah K.
    Cooper, Stacy L.
    Cooper, Todd M.
    Hijiya, Nobuko
    Sulis, Maria Luisa
    Shukla, Neerav N.
    Magee, Jeffrey A.
    Mullighan, Charles G.
    Burke, Michael J.
    Luskin, Marlise R.
    Mar, Brenton G.
    Jacobson, Matthew P.
    Harris, Marian H.
    Stegmaier, Kimberly
    Place, Andrew E.
    Pikman, Yana
    CLINICAL CANCER RESEARCH, 2023, 29 (22) : 4613 - 4626
  • [25] Integration Analysis of Single-Cell Multi-Omics Reveals Prostate Cancer Heterogeneity
    Bian, Xiaojie
    Wang, Wenfeng
    Abudurexiti, Mierxiati
    Zhang, Xingming
    Ma, Weiwei
    Shi, Guohai
    Du, Leilei
    Xu, Midie
    Wang, Xin
    Tan, Cong
    Sun, Hui
    He, Xiadi
    Zhang, Chenyue
    Zhu, Yao
    Zhang, Min
    Ye, Dingwei
    Wang, Jianhua
    ADVANCED SCIENCE, 2024, 11 (18)
  • [26] Leukemia-initiating Cells in T-Cell Acute Lymphoblastic Leukemia
    Tan, Shi Hao
    Bertulfo, Fatima Carla
    Sanda, Takaomi
    FRONTIERS IN ONCOLOGY, 2017, 7
  • [27] Revisiting β-Catenin Signaling in T-Cell Development and T-Cell Acute Lymphoblastic Leukemia
    Bigas, Anna
    Guillen, Yolanda
    Schoch, Leonie
    Arambilet, David
    BIOESSAYS, 2020, 42 (02)
  • [28] Nelarabine for the Treatment of Patients with Relapsed or Refractory T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
    DeAngelo, Daniel J.
    HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA, 2009, 23 (05) : 1121 - +
  • [29] Integrating microRNA and mRNA expression in rapamycin-treated T-cell acute lymphoblastic leukemia
    Chen, Xi
    Guo, Zhibo
    Fan, Shengjin
    Sun, Lili
    Li, Huibo
    Zhou, Jin
    Li, Yinghua
    PATHOLOGY RESEARCH AND PRACTICE, 2019, 215 (08)
  • [30] A case of T-cell acute lymphoblastic leukemia after treatment of acute promyelocytic leukemia
    Bee, PC
    Gan, GG
    Sangkar, JV
    Teh, A
    Goh, KY
    INTERNATIONAL JOURNAL OF HEMATOLOGY, 2004, 79 (04) : 358 - 360