Mutations in protein-coding genes are well established as the basis for human cancer, yet how alterations within noncoding genome, a substantial fraction of which contain cis-regulatory elements (CRE), contribute to cancer pathophysiology remains elusive. Here, we developed an integrative approach to systematically identify and characterize noncoding regulatory variants with functional consequences in human hematopoietic malignancies. Combining targeted resequencing of hematopoietic lineage-associated CREs and mutation discovery, we uncovered 1,836 recurrently mutated CREs containing leukemia-associated noncoding variants. By enhanced CRISPR/dCas9-based CRE perturbation screening and functional analyses, we identified 218 variant-associated oncogenic or tumor-suppressive CREs in human leukemia. Noncoding variants at KRAS and PER2 enhancers reside in proximity to nuclear receptor (NR) binding regions and modulate transcriptional activities in response to NR signaling in leukemia cells. NR binding sites frequently colocalize with noncoding variants across cancer types. Hence, recurrent noncoding variants connect enhancer dysregulation with nuclear receptor signaling in hematopoietic malignancies. SIGNIFICANCE: We describe an integrative approach to identify noncoding variants in human leukemia, and reveal cohorts of variant-associated oncogenic and tumor-suppressive cis-regulatory elements including KRAS and PER2 enhancers. Our findings support a model in which noncoding regulatory variants connect enhancer dysregulation with nuclear receptor signaling to modulate gene programs in hematopoietic malignancies.See related commentary by van Galen, p. 646.This article is highlighted in the In This Issue feature, p. 627.

中文翻译：

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非编码变体将增强子失调与造血系统恶性肿瘤中的核受体信号传导联系起来。

蛋白质编码基因的突变已被公认为人类癌症的基础，但非编码基因组内的改变（其中很大一部分包含顺式调节元件（CRE））如何导致癌症病理生理学仍然难以捉摸。在这里，我们开发了一种综合方法来系统地识别和表征在人类造血系统恶性肿瘤中具有功能后果的非编码调节变体。结合造血谱系相关 CRE 的靶向重测序和突变发现，我们发现了 1,836 个包含白血病相关非编码变体的反复突变 CRE。通过增强的基于 CRISPR/dCas9 的 CRE 扰动筛选和功能分析，我们在人类白血病中鉴定了 218 个与变异相关的致癌或肿瘤抑制 CRE。KRAS 和 PER2 增强子的非编码变体位于核受体 (NR) 结合区附近，并调节转录活性以响应白血病细胞中的 NR 信号。NR 结合位点经常与癌症类型的非编码变体共定位。因此，在造血系统恶性肿瘤中，复发性非编码变异将增强子失调与核受体信号传导联系起来。意义：我们描述了一种识别人类白血病非编码变异的综合方法，并揭示了与变异相关的致癌和抑制肿瘤的顺式调节元件的队列，包括 KRAS 和 PER2 增强子。我们的研究结果支持一种模型，其中非编码调节变异将增强子失调与核受体信号传导联系起来，以调节造血系统恶性肿瘤中的基因程序。参见 van Galen 的相关评论，p。646. 这篇文章在本期专题中突出显示，第。627.