Regulatory network of GATA3 in pediatric acute lymphoblastic leukemia

• DOI: 10.18632/oncotarget.16424
• Publication Date: 2017-03-21T16:25:50Z
• Authors: Qianqian Hou; Fei Liao; Shouyue Zhang; Duyu Zhang; Yan Zhang; Xueyan Zhou; Xuyang Xia; Yuanxin Ye; Hanshuo Yang; Zhaozhi Li; Leiming Wang; Xi Wang; Zhigui Ma; Yiping Zhu; Liang Ouyang; Yuelan Wang; Hui Zhang; Li Yang; Heng Xu; Yang Shu
• Keywords: 0301 basic medicine; B-Lymphocytes; Gene Expression Regulation, Leukemic; Membrane Proteins; GATA3 Transcription Factor; Precursor Cell Lymphoblastic Leukemia-Lymphoma; STAT4 Transcription Factor; Polymorphism, Single Nucleotide; Epigenesis, Genetic; 3. Good health; Cohort Studies; DNA-Binding Proteins; 03 medical and health sciences; Cell Line, Tumor; Humans; Gene Regulatory Networks; Child; Research Paper; Genome-Wide Association Study

GATA3 polymorphisms were reported to be significantly associated with susceptibility of pediatric B-lineage acute lymphoblastic leukemia (ALL), by impacting on GATA3 expression. We noticed that ALL-related GATA3 polymorphism located around in the tissue-specific enhancer, and significantly associated with GATA3 expression. Although the regulatory network of GATA3 has been well reported in T cells, the functional status of GATA3 is poorly understood in B-ALL. We thus conducted genome-wide gene expression association analyses to reveal expression associated genes and pathways in nine independent B-ALL patient cohorts. In B-ALL patients, 173 candidates were identified to be significantly associated with GATA3 expression, including some reported GATA3-related genes (e.g., ITM2A) and well-known tumor-related genes (e.g., STAT4). Some of the candidates exhibit tissue-specific and subtype-specific association with GATA3. Through overexpression and down-regulation of GATA3 in leukemia cell lines, several reported and novel GATA3 regulated genes were validated. Moreover, association of GATA3 expression and its targets can be impacted by SNPs (e.g., rs4894953), which locate in the potential GATA3 binding motif. Our findings suggest that GATA3 may be involved in multiple tumor-related pathways (e.g., STAT/JAK pathway) in B-ALL to impact leukemogenesis through epigenetic regulation.