Abstract 6213: Chromatin accessibility landscape of pediatric high-risk B-cell acute lymphoblastic leukemia

Abstract

Abstract B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy. Although overall cure rate has exceeded 90%, the prognosis of high-risk B-ALL remains poor. Genome sequencing studies have revealed key genetic aberrations in B-ALL. But driver remains unclear in 8% of B-ALL for leukemogenesis, and 40% of high-risk B-ALL for drug resistance. Epigenetic mechanisms contributing to leukemia have recently been recognized, including histone modification and methylation. To date, a comprehensive landscape of chromatin accessibility in B-ALL is still lacking. Here, we performed Assays for Transposase Accessible Chromatin using sequencing (ATAC-seq) on a total of 61 high-risk B-ALLs treated at Shanghai Children’s Medical Center, including major B-ALL subtypes. We generated 144 high quality chromatin accessibility profiles from 79 tumors, including 18 diagnosis-relapse paired tumors as well as 11 diagnosis and 32 relapsed tumors. We observed significantly higher chromatin accessibility in B-ALL as compared to normal B-cells. Functional chromatin state annotation showed a median of 27.1% open chromatin regions (OCRs) in B-ALL were constituted from quiescent regions that were absent for known histone modifications, indicating unveiled role of quiescent regions in B-ALL. We further investigated the allelic imbalanced chromatin accessibility in 32 B-ALL with matched ATAC-seq and whole genome sequencing data. Unexpectedly, we found a median of 10.8% of OCRs showed imbalanced accessibility between two heterozygous alleles. Moreover, the adjacent imbalanced OCRs tend to be in the same topologically associating domain, suggesting the transcription regulation from chromatin accessibility was constrained within 3-D genome architecture. We next looked into the OCRs among B-ALL subtypes. Consistent with the regulatory role of chromatin accessibility on gene transcription, we found subtype specific pattern of OCRs in B-ALL, with open regions from enhancer and bivalent chromatin states showed more power in subtype discrimination. A total of 15516 out of 765788 (2.03%) peaks were identified as subtype specific OCRs. Motif analysis associated these regions to 212 transcription factors (TFs). Consistently, genes regulated by these TFs also exhibited subtype specific expression. Finally, we analyzed differences in OCRs between diagnosis (D) and relapse (R) in each B-ALL subtype. Only 2.44% D-R differential peaks were shared between any two subtypes, suggesting subtype specific role of chromatin accessibility in relapse. Potential target genes were further identified with quantitative trait loci analysis. With data from DepMap project, we verified that the expression of the target genes identified was associated with drug response. These data unveiled potential role of chromatin accessibility in high-risk B-ALL and the treatment response of this malignancy. Citation Format: Han Wang, Huiying Sun, Bilin Liang, Fang Zhang, Fan Yang, Bowen Cui, Lixia Ding, Ronghua Wang, Yanjing Tang, Jianan Rao, Wenting Hu, Shuang Zhao, Wenyan Wu, Benshang Li, Jingyan Tang, Shuhong Shen, Yu Liu. Chromatin accessibility landscape of pediatric high-risk B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6213.