Identification of genomic and epigenomic determinants of drug resistance provides important insights for improving cancer treatment. Using agnostic genome-wide interrogation of messenger RNA and microRNA (miRNA) expression, DNA methylation, single-nucleotide polymorphisms, copy number alterations and single-nucleotide variants/indels in primary human acute lymphoblastic leukemia cells, we identified 463 genomic features associated with glucocorticoid resistance. Gene-level aggregation identified 118 overlapping genes, 15 of which were confirmed by genome-wide CRISPR screen. Collectively, this identified 30 of 38 (79%) known glucocorticoid-resistance genes/miRNAs and all 38 known resistance pathways, while revealing 14 genes not previously associated with glucocorticoid resistance. Single-cell RNA-sequencing and network-based transcriptomic modeling corroborated the top previously undiscovered gene, CELSR2. Manipulation of CELSR2 recapitulated glucocorticoid resistance in human leukemia cell lines and revealed a synergistic drug combination (prednisolone and venetoclax) that mitigated resistance in mouse xenograft models. These findings illustrate the power of an integrative genomic strategy for elucidating genes and pathways conferring drug resistance in cancer cells.

耐药性的基因组和表观基因组决定因素的鉴定为改善癌症治疗提供了重要的见解。通过对原代人急性淋巴细胞白血病细胞中的信使 RNA 和 microRNA (miRNA) 表达、DNA 甲基化、单核苷酸多态性、拷贝数改变和单核苷酸变异/插入缺失进行不可知的全基因组询问，我们鉴定了 463 个与糖皮质激素相关的基因组特征反抗。基因水平聚合鉴定出 118 个重叠基因，其中 15 个通过全基因组 CRISPR 筛选得到证实。总的来说，这鉴定了 38 个已知糖皮质激素耐药基因/miRNA 中的 30 个 (79%) 以及所有 38 个已知耐药途径，同时揭示了 14 个以前与糖皮质激素耐药无关的基因。单细胞 RNA 测序和基于网络的转录组模型证实了之前未被发现的顶级基因CELSR2 。对CELSR2的操作重现了人类白血病细胞系中的糖皮质激素耐药性，并揭示了一种协同药物组合（泼尼松龙和维奈托克），可以减轻小鼠异种移植模型中的耐药性。这些发现说明了综合基因组策略在阐明癌细胞耐药性基因和途径方面的力量。