Inherited GATA3 variant associated with positive minimal residual disease in childhood B‐cell acute lymphoblastic leukemia via asparaginase resistance

• Published in: Clinical and translational medicine Vol. 11; no. 8; pp. e507 - n/a
• Main Authors: Li, Chunjie, Liang, Wenyi, He, Yingyi, Zhao, Xinying, Qian, Jiabi, Li, Ziping, Jiang, Chuang, Zheng, Qingqing, Fu, Xiangmeng, Zhang, Weina, Liu, Haiyan, Sun, Xin, Qian, Maoxiang, Zhang, Hui
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.08.2021; John Wiley and Sons Inc; Wiley
• Subjects: Asparaginase - genetics; Asparaginase - metabolism; Autophagy; Child; Children & youth; Clinical outcomes; Conflicts of interest; CRISPR; Data analysis; GATA3 Transcription Factor - genetics; GATA3 Transcription Factor - metabolism; Humans; Letter to Editor; Leukemia; Medical prognosis; Neoplasm, Residual; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.507

Using an additive logistic regression model, we found that GATA3 rs3824662 A allele and rs3781093 C allele were significantly associated with minimal residual disease (MRD) positivity on day 46 (p = 0.039, odds ratio [OR] = 1.54 [95% confidence interval: 1.01–2.36], and p = 0.036, OR = 1.55 [1.03–2.39] in dichotomous analysis, respectively; p = 0.02 and p = 0.018 in ordinal analysis, respectively) (Figure 1B,C, Figures S1–S3). SEE PDF] To investigate the biological function of the germline GATA3 variant, we examined the chromatin state of this genomic region across different hematopoietic cell types by ChromHMM.4 Across 11 hematopoietic cells, we interestingly found that rs3824662 was resided inside regions with weak enhancer activity in hematopoietic tissues (Figure 2A), suggesting the cis-transcriptional regulation role. SEE PDF] We speculated that active GATA3 expression might lead to drug resistance, a major contributor to MRD.5 To test this hypothesis, we retrieved a series of expression profiling array datasets from the NCBI GEO database and investigated a correlation between GATA3 expression and the drug sensitivity of primary B-ALL cells.6 High levels of GATA3 expression were significantly correlated with l-asparaginase (l-Asp, p < 0.0001) (Figure 3A, Figures S6 and S7). [...]we inhibited autophagosome turnover in 697 cells with chloroquine diphosphate salt (CQ) and found that GATA3-induced l-Asp resistance was almost completely rescued (Figure 4D), suggesting the potential mechanism of GATA3 mediated l-Asp resistance via activation of autophagy.